APLNR

Summary

APLNR (apelin receptor, HGNC:339) is a protein-coding gene on chromosome 11q12.1, encoding Apelin receptor (P35414). G protein-coupled receptor for peptide hormones apelin (APLN) and apelin receptor early endogenous ligand (APELA/ELA), that plays a role in the regulation of normal cardiovascular function and fluid homeostasis.

This gene encodes a member of the G protein-coupled receptor gene family. The encoded protein is related to the angiotensin receptor, but is actually an apelin receptor that inhibits adenylate cyclase activity and plays a counter-regulatory role against the pressure action of angiotensin II by exerting hypertensive effect. It functions in the cardiovascular and central nervous systems, in glucose metabolism, in embryonic and tumor angiogenesis and as a human immunodeficiency virus (HIV-1) coreceptor. Two transcript variants resulting from alternative splicing have been identified.

Source: NCBI Gene 187 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 73 total — 2 likely-pathogenic
• Druggable target: yes — 9 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005161

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:339
Approved symbol	APLNR
Name	apelin receptor
Location	11q12.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ90771, APJ, APJR
Ensembl gene	ENSG00000134817
Ensembl biotype	protein_coding
OMIM	600052
Entrez	187

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 nonsense_mediated_decay, 1 protein_coding

ENST00000257254, ENST00000606794

RefSeq mRNA: 1 — MANE Select: NM_005161 NM_005161

CCDS: CCDS7950

Canonical transcript exons

ENST00000606794 — 1 exons

Exon	Start	End
ENSE00003695344	57233591	57237250

Expression profiles

Bgee: expression breadth ubiquitous, 232 present calls, max score 98.97.

FANTOM5 (CAGE): breadth broad, TPM avg 5.3194 / max 459.7198, expressed in 342 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
119711	4.2072	310
119712	0.5704	176
119710	0.2681	115
119714	0.1297	53
119715	0.0720	23
119713	0.0719	40

Top tissues by expression

279 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cranial nerve II	UBERON:0000941	98.97	gold quality
inferior olivary complex	UBERON:0002127	98.55	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.79	gold quality
tendon of biceps brachii	UBERON:0008188	96.68	gold quality
ventral tegmental area	UBERON:0002691	95.33	gold quality
spinal cord	UBERON:0002240	94.97	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.65	gold quality
CA1 field of hippocampus	UBERON:0003881	94.48	gold quality
medulla oblongata	UBERON:0001896	94.30	gold quality
left ventricle myocardium	UBERON:0006566	92.80	gold quality
spleen	UBERON:0002106	92.50	gold quality
inferior vagus X ganglion	UBERON:0005363	91.56	gold quality
midbrain	UBERON:0001891	90.94	gold quality
substantia nigra	UBERON:0002038	90.93	gold quality
apex of heart	UBERON:0002098	90.81	gold quality
cardiac muscle of right atrium	UBERON:0003379	90.55	gold quality
hypothalamus	UBERON:0001898	90.44	gold quality
superior vestibular nucleus	UBERON:0007227	89.49	gold quality
vena cava	UBERON:0004087	89.24	gold quality
placenta	UBERON:0001987	88.55	gold quality
subthalamic nucleus	UBERON:0001906	88.12	gold quality
myocardium	UBERON:0002349	88.08	gold quality
amygdala	UBERON:0001876	87.57	gold quality
cardia of stomach	UBERON:0001162	87.55	gold quality
corpus callosum	UBERON:0002336	87.32	gold quality
Ammon’s horn	UBERON:0001954	86.61	gold quality
dorsal plus ventral thalamus	UBERON:0001897	86.22	gold quality
medial globus pallidus	UBERON:0002477	85.71	gold quality
parietal pleura	UBERON:0002400	85.66	gold quality
gall bladder	UBERON:0002110	84.77	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	1332.50
E-MTAB-9906	yes	982.17
E-GEOD-109979	yes	345.44
E-MTAB-8205	yes	301.54
E-HCAD-10	yes	44.41
E-MTAB-6701	yes	14.52
E-ANND-3	yes	5.28
E-CURD-112	no	3.55
E-MTAB-6678	no	2.43

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
GJA4	Repression
GJA5	Repression
KLF2	Unknown
VCAM1	Repression

Upstream regulators (CollecTRI, top): SP1

miRNA regulators (miRDB)

90 targeting APLNR, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-149-3P	99.72	68.22	3963

Literature-anchored findings (GeneRIF, showing 40)

• internalization and recycling, in stably expressing indicator cells, human neurons, primary CNS microvascular endothelial cells, and astrocytes (PMID:12667811)
• results demonstrate that apelin receptor exhibits nuclear localization in brain, distinct cell-dependent mechanisms for the nuclear transport of apelin receptors, and disruption of nuclear signal sequence disrupts its nuclear translocation (PMID:14645236)
• second 10 residues of the N-terminal domain of APJ are critical for association with apelin, while the first 20 amino acids play an important role in supporting cell-cell fusion mediated by HIV-1 gp120 (PMID:14675627)
• APJ exerts the hypotensive effect in vivo and plays a counterregulatory role against the pressor action of angiotensin II (PMID:15087458)
• reported the presence of APJ receptor-like immunoreactivity on cardiomyocytes, vascular smooth muscle cells and endothelial cells and the presence of apelin-like immunoreactivity in secretory vesicles of vascular endothelial cells (PMID:15664671)
• apelin and APJ are expressed in preeclamptic placentas and may have a role in development of preeclampsia (PMID:17128405)
• The results indicate that the SNP in the AGTRL1 gene is associated with the susceptibility to brain infarction. (PMID:17309882)
• Apelin and APJ expression is highly upregulated in microvascular proliferations of brain tumors such as malignant gliomas. (PMID:17412318)
• In conclusion, the ERK1/2, but not p38 MAPK pathway is activated by apelin-13 through coupling of human APJ to Gi2-protein, which contributes to cellular responses. (PMID:18401529)
• Nuclear magnetic resonance and circular dichroism spectroscopy results are presented for a variety of apelin peptides at both physiological and low temperatures allowing determination of the bioactive structure of apelin. (PMID:19123778)
• genetic variation within apelin and AGTRL1 likely contributes to essential hypertension, BMI and the onset age of hypertension (PMID:19307984)
• Endothelial expression of apelin receptors is observed during the embryonic formation of blood vessels. The apelin system is both involved in physiological angiogenesis and pathological neoangiogenesis. Review. (PMID:19527631)
• AGTRL1 polymorphism is not associated with coronary artery disease. (PMID:19680269)
• No association between APLNR mRNA expression and gestational diabetes. (PMID:19926159)
• While apelin/APJ myocardial expression decreases, apelin plasma levels increase in left ventricular hypertrophy (PMID:20055692)
• Aortic valve stenosis is characterized by an up-regulation of the apelin-APJ signaling pathway. (PMID:20099713)
• Single nucleotide polymorphisms of the APLNR gene were significantly associated with diastolic blood pressure and mean arterial blood pressure responses to low-sodium intervention. (PMID:20125035)
• The apelin/APJ system may be involved in retinal neovascularization during the development of proliferative diabetic retinopathy. (PMID:20220056)
• Our study indicates that genetic variation of APLN-APJ and ACE2 may influence BP response to potassium intake. (PMID:20224560)
• These observations revealed a novel ligand-dependent targeting of the apelin receptor to beta-arrestin-associated and -dissociated trafficking pathways and a role for different Rab proteins to direct these pathways. (PMID:20353754)
• found robust haplotype-based and haplotype-phenotype associations of four well characterized polymorphisms in apelin-AGTRL1 system with hypertension and related phenotypes (PMID:20485192)
• These findings bring new insights into apelin receptor activation and show that Phe(255) and Trp(259), by interacting with the C-terminal Phe of the pyroglutamyl form of apelin 13 (pE13F) or K17F, are crucial for apelin receptor internalization. (PMID:20675385)
• Disruption of apelin-APJ signaling can exacerbate pulmonary hypertension mediated by decreased activation of AMP-activated kinase and eNOS. (PMID:21233449)
• demonstrated that non-activated APJ may suppress Ang II-AT(1) signaling, whereas this ligand-independent function was diminished with apelin activation (PMID:21412239)
• hypoxia and inflammatory factors could play a major role in the activation of the hepatic apelin system leading to angiogenic and fibroproliferative response occurring in chronic liver disease. (PMID:21450694)
• the novel peptide apelin and its receptor APJ can induce the morphological and functional maturation of blood vessels in tumors (PMID:22037214)
• There was an increased frequency of the G212 allele of AJP receptor in patients with hypertension in respect to patients without hypertension. (PMID:22109355)
• Apelin may be associated with proliferative vasculopathy in systemic sclerosis. (PMID:22112232)
• APELIN promotes hematopoiesis from human embryonic stem cells. (PMID:22611158)
• Apelin/APJ pathway serves as a critical intermediary that links statin to its pleiotropic effects in regulating endothelial gene targets and function. (PMID:22995518)
• Interactive effects of genetic defects in apelin/APJ pathway might confer a potential risk in Chinese hypertensive patients. (PMID:23226564)
• Introduce a new correlative NMR spectroscopy and computational biochemistry methodology and demonstrate its utility in providing some of the first high-resolution structural information for a peptide-activated apelin receptor transmembrane domain. (PMID:23438363)
• functional role of the apelin–APJ system likely in early gestation (PMID:23844873)
• REVIEW: Growing evidence shows that apelin/APJ system functions as a critical mediator of cardiovascular homeostasis and is involved in the pathophysiology of cardiovascular diseases. (PMID:24055369)
• AGTRL1 genetic polymorphisms might contribute to the development of hypertension independently and/or through complex interaction. (PMID:24465893)
• APJ and B1R can form heterodimers in transfected HEK293 cells and activations of APJ and B1R could up-regulate eNOS phosphorylation (PMID:24686079)
• obese (especially diabese) youngsters demonstrated lower serum apelin levels; the G212A polymorphism of the APLNR gene was found to exert a favourable effect on circulating apelin levels in childhood obesity (PMID:25060841)
• ERG and APLNR are essential for endothelial homeostasis in venules in the lung and that perturbation in ERG-APLNR signaling is crucial for the development of pulmonary veno-occlusive disease. (PMID:25062690)
• serine 348 on the apelin receptor is a novel regulatory phosphorylation site in apelin-13-induced G protein-independent biased signaling (PMID:25271156)
• Apelin-APJ is overexpressed, and works as a signal for arteriogenesis in HCC. (PMID:25275024)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	aplnr2	ENSDARG00000004447
mus_musculus	Aplnr	ENSMUSG00000044338
rattus_norvegicus	Aplnr	ENSRNOG00000009227

Paralogs (7): BDKRB1 (ENSG00000100739), AGTR1 (ENSG00000144891), GPR15 (ENSG00000154165), BDKRB2 (ENSG00000168398), GPR25 (ENSG00000170128), RXFP4 (ENSG00000173080), AGTR2 (ENSG00000180772)

Protein

Protein identifiers

Apelin receptor — P35414 (reviewed: P35414)

Alternative names: Angiotensin receptor-like 1, G-protein coupled receptor APJ, G-protein coupled receptor HG11

All UniProt accessions (1): P35414

UniProt curated annotations — full annotation on UniProt →

Function. G protein-coupled receptor for peptide hormones apelin (APLN) and apelin receptor early endogenous ligand (APELA/ELA), that plays a role in the regulation of normal cardiovascular function and fluid homeostasis. When acting as apelin receptor, activates both G(i) protein pathway that inhibits adenylate cyclase activity, and the beta-arrestin pathway that promotes internalization of the receptor. APLNR/APJ also functions as mechanoreceptor that is activated by pathological stimuli in a G-protein-independent fashion to induce beta-arrestin signaling, hence eliciting cardiac hypertrophy. However, the presence of apelin ligand blunts cardiac hypertrophic induction from APLNR/APJ on response to pathological stimuli. Plays a key role in early development such as gastrulation, blood vessels formation and heart morphogenesis by acting as a APELA receptor. May promote angioblast migration toward the embryonic midline, i.e. the position of the future vessel formation, during vasculogenesis. Promotes sinus venosus (SV)-derived endothelial cells migration into the developing heart to promote coronary blood vessel development. Also plays a role in various processes in adults such as regulation of blood vessel formation, blood pressure, heart contractility and heart failure. (Microbial infection) Alternative coreceptor with CD4 for HIV-1 infection; may be involved in the development of AIDS dementia.

Subunit / interactions. Homodimer; dimerization inhibits APLNR-mediated G protein and beta-arrestin signaling pathways compared to monomeric APLNR.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in heart, brain, kidney, stomach, spleen, thymus, lung, ovary, small intestine and colon, adipose tissues and pancreas. Expressed in glial cells, astrocytes and neuronal subpopulations. Expressed in embryonic (ESCs) and induced (iPSCs) pluripotent stem cells.

Domain organisation. The hydrogen bond between Asn-46 and Asp-75 is crucial for beta-arrestin signaling induced by APLN/apelin-13.

Similarity. Belongs to the G-protein coupled receptor 1 family.

RefSeq proteins (1): NP_005152* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR003904	Apelin_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR050119	CCR1-9-like	Family

Pfam: PF00001

UniProt features (77 total): mutagenesis site 22, helix 16, topological domain 8, turn 8, transmembrane region 7, strand 5, compositionally biased region 2, site 2, glycosylation site 2, disulfide bond 2, chain 1, region of interest 1, sequence variant 1

Structure

Experimental structures (PDB)

37 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9LQY	ELECTRON MICROSCOPY	2.4
9LR1	ELECTRON MICROSCOPY	2.5
8S4D	X-RAY DIFFRACTION	2.58
5VBL	X-RAY DIFFRACTION	2.6
8XZH	ELECTRON MICROSCOPY	2.6
9LQT	ELECTRON MICROSCOPY	2.6
9LQZ	ELECTRON MICROSCOPY	2.6
7SUS	X-RAY DIFFRACTION	2.7
8XZI	ELECTRON MICROSCOPY	2.7
9LQU	ELECTRON MICROSCOPY	2.7
9LQW	ELECTRON MICROSCOPY	2.7
9LQX	ELECTRON MICROSCOPY	2.7
9LR3	ELECTRON MICROSCOPY	2.8
9JH3	ELECTRON MICROSCOPY	2.93
8XQJ	ELECTRON MICROSCOPY	2.95
8XZF	ELECTRON MICROSCOPY	3
8XZJ	ELECTRON MICROSCOPY	3
8Z74	ELECTRON MICROSCOPY	3.01
9LR2	ELECTRON MICROSCOPY	3.1
8Z7J	ELECTRON MICROSCOPY	3.12
8XQF	ELECTRON MICROSCOPY	3.13
7W0P	ELECTRON MICROSCOPY	3.16
6KNM	X-RAY DIFFRACTION	3.2
8XZG	ELECTRON MICROSCOPY	3.2
9KUV	ELECTRON MICROSCOPY	3.21
8XQI	ELECTRON MICROSCOPY	3.25
8XQE	ELECTRON MICROSCOPY	3.48
9KUW	ELECTRON MICROSCOPY	3.49
7W0L	ELECTRON MICROSCOPY	3.57
9KUX	ELECTRON MICROSCOPY	3.57

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35414-F1	82.11	0.58

Antibody-complex structures (SAbDab): 15 — 6KNM, 7W0L, 7W0M, 7W0N, 7W0O, 7W0P, 8XQE, 8XQF, 8XQJ, 8XZF, 8XZH, 8XZI, 8XZJ, 8Z74, 8Z7J

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 85 (required for apela and apln/apelin-13 interaction and signaling); 168 (required for apela and apln/apelin-13 interaction and signaling)

Disulfide bonds (2): 19–281, 102–181

Glycosylation sites (2): 15, 175

Mutagenesis-validated functional residues (22):

Position	Phenotype
19	decreased apln/apelin-13 potency.
35	decreased apln/apelin-13 potency. decreased g(i) and beta-arresting signalings after apln/apelin-13 induction.
46	loss of beta-arrestin recrutment after apln/apelin-13 induction. small decrease in g(i) signaling after apln/apelin-13 i
85	loss of apela signaling. loss of apln/apelin-13 signaling.
88	decreased apela potency. no change in apln/apelin-13 potency.
93	decreased apela potency. no change in apln/apelin-13 potency.
97	decreased protein expression level and camp-dependent pathway. decreased protein expression level and camp-dependent pat
98	decreased protein expression level. decreased protein expression level; when associated with a-97, a-99, a-100 and a-101
99	no change in protein expression level. decreased protein expression level; when associated with a-97, a-98, a-100 and a-
100	no change in protein expression level. decreased protein expression level; when associated with a-97, a-98, a-99 and a-1
101	decreased homdimerization, no change in apela potency, increased g protein and beta-arrestin signaling pathways. decreas
109	strong decrease in beta-arresting signaling after apln/apelin-13 induction. no change in g(i) signaling after apln/apeli
110	no change in apela potency. no change in apln/apelin-13 potency. decreased g(i) signaling and no change in beta-arrestin
116	small decrease in g(i) signaling after apln/apelin-13 induction. decreased beta-arresting signaling after apln/apelin-13
168	loss of apela signaling. loss of apela signaling.
173	decreased apela potency. no change in apln/apelin-13 potency.
183	decreased apela potency. no change in apln/apelin-13 potency.
185	decreased apln/apelin-13 potency.
268	strong decrease in beta-arresting signaling after apln/apelin-13 induction. no change in g(i) signaling after apln/apeli
271	decreased apln/apelin-13 potency.
299	decreased g(i) signalingafter apln/apelin-13 induction. no change in beta-arresting signaling after apln/apelin-13 induc
302	no change in g(i) signaling after apln/apelin-13 induction. decreased beta-arresting signaling after apln/apelin-13 indu

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-418594	G alpha (i) signalling events
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-388396	GPCR downstream signalling
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 276 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_G_PROTEIN_COUPLED_RECEPTOR_INTERNALIZATION, RNGTGGGC_UNKNOWN, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_VENTRICULAR_SEPTUM_MORPHOGENESIS, GOBP_CORONARY_VASCULATURE_DEVELOPMENT, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, GOBP_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOBP_ENDOCARDIAL_CUSHION_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY

GO Biological Process (32): angiogenesis (GO:0001525), blood vessel development (GO:0001568), vasculogenesis (GO:0001570), vasculature development (GO:0001944), heart looping (GO:0001947), atrioventricular valve development (GO:0003171), endocardial cushion formation (GO:0003272), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), gastrulation (GO:0007369), heart development (GO:0007507), adult heart development (GO:0007512), regulation of gene expression (GO:0010468), negative regulation of gene expression (GO:0010629), vascular associated smooth muscle cell differentiation (GO:0035886), aorta development (GO:0035904), obsolete negative regulation of cAMP-mediated signaling (GO:0043951), positive regulation of angiogenesis (GO:0045766), regulation of body fluid levels (GO:0050878), positive regulation of release of sequestered calcium ion into cytosol (GO:0051281), apelin receptor signaling pathway (GO:0060183), ventricular septum morphogenesis (GO:0060412), venous blood vessel development (GO:0060841), coronary vasculature development (GO:0060976), negative regulation of cardiac muscle hypertrophy in response to stress (GO:1903243), positive regulation of cardiac muscle hypertrophy in response to stress (GO:1903244), positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis (GO:1903589), regulation of gap junction assembly (GO:1903596), positive regulation of G protein-coupled receptor internalization (GO:1904022), G protein-coupled receptor internalization (GO:0002031), signal transduction (GO:0007165), positive regulation of cardiac muscle hypertrophy (GO:0010613)

GO Molecular Function (6): G protein-coupled receptor activity (GO:0004930), G protein-coupled peptide receptor activity (GO:0008528), signaling receptor activity (GO:0038023), apelin receptor activity (GO:0060182), mechanoreceptor activity (GO:0140897), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Signaling by GPCR	2
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1
Signal Transduction	1
GPCR ligand binding	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
blood vessel morphogenesis	2
anatomical structure formation involved in morphogenesis	2
vasculature development	2
circulatory system development	2
G protein-coupled receptor activity	2
gene expression	2
transmembrane signaling receptor activity	2
anatomical structure development	1
cell differentiation	1
system development	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
heart valve development	1
endocardial cushion morphogenesis	1
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
ectoderm formation	1
endoderm formation	1
mesoderm formation	1
embryonic morphogenesis	1
animal organ development	1
heart development	1
regulation of macromolecule biosynthetic process	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
smooth muscle cell differentiation	1
artery development	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
regulation of biological quality	1
release of sequestered calcium ion into cytosol	1
regulation of release of sequestered calcium ion into cytosol	1
positive regulation of calcium ion transmembrane transport	1
G protein-coupled receptor signaling pathway	1
peptide receptor activity	1
molecular transducer activity	1
G protein-coupled peptide receptor activity	1
apelin receptor signaling pathway	1

Protein interactions and networks

STRING

1760 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APLNR	APLN	Q9ULZ1	999
APLNR	APELA	P0DMC3	994
APLNR	JAK1	P23458	900
APLNR	F13A1	P00488	777
APLNR	KNG1	P01042	756
APLNR	AGT	P01019	730
APLNR	ARRB2	P32121	684
APLNR	ADGRL3	Q9HAR2	573
APLNR	SUCLG2	Q96I99	567
APLNR	GRM8	O00222	561
APLNR	ADGRB3	O60242	549
APLNR	GNAO1	P09471	541
APLNR	RETN	Q9HD89	530
APLNR	RETNLB	Q9BQ08	529
APLNR	GRK2	P25098	516

IntAct

45 interactions, top by confidence:

A	B	Type	Score
AGTR1	APLNR	psi-mi:“MI:0915”(physical association)	0.710
AGTR1	APLNR	psi-mi:“MI:2364”(proximity)	0.710
APLNR	AGTR1	psi-mi:“MI:0915”(physical association)	0.710
APLNR	OPRK1	psi-mi:“MI:0403”(colocalization)	0.650
APLNR	OPRK1	psi-mi:“MI:0915”(physical association)	0.650
OPRK1	APLNR	psi-mi:“MI:2364”(proximity)	0.650
OPRK1	APLNR	psi-mi:“MI:0915”(physical association)	0.650
GJB2	APLNR	psi-mi:“MI:0915”(physical association)	0.560
APLNR	HCRTR1	psi-mi:“MI:0915”(physical association)	0.560
HCRTR1	APLNR	psi-mi:“MI:0915”(physical association)	0.560
HCRTR1	APLNR	psi-mi:“MI:0403”(colocalization)	0.560
APLNR	HCRTR1	psi-mi:“MI:0403”(colocalization)	0.560
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
APLNR	SLC33A1	psi-mi:“MI:0914”(association)	0.530
ARRB2	APLNR	psi-mi:“MI:0915”(physical association)	0.440
ARRB2	APLNR	psi-mi:“MI:0403”(colocalization)	0.440

BioGRID (294): AKR1D1 (Affinity Capture-MS), TTI2 (Affinity Capture-MS), CCDC109B (Affinity Capture-MS), SLC25A24 (Affinity Capture-MS), ORC5 (Affinity Capture-MS), TMEM161B (Affinity Capture-MS), PDS5B (Affinity Capture-MS), ABCD1 (Affinity Capture-MS), ADCK1 (Affinity Capture-MS), HIP1R (Affinity Capture-MS), MFSD9 (Affinity Capture-MS), MTX3 (Affinity Capture-MS), SLC25A23 (Affinity Capture-MS), PDXDC1 (Affinity Capture-MS), TUBGCP3 (Affinity Capture-MS)

ESM2 similar proteins: O02662, O08726, O43603, O60755, O70432, O88626, O88853, O88854, O95665, O97666, P0C5I1, P13945, P25962, P26255, P30729, P30935, P30936, P31387, P31388, P35365, P35414, P46626, P49683, P50406, P51436, P70310, Q28524, Q3ZC80, Q4EW11, Q5IS65, Q60483, Q63384, Q64121, Q6TLJ0, Q6VMN6, Q7TQP4, Q8MJV2, Q8TDU9, Q91V45, Q924U1

Diamond homologs: A0A4W3GG95, A0A6I8PUB9, B2GV46, B5X337, D4A7K7, E7FEL0, E9QJ73, F8VQN3, O00270, O08726, O08858, O14842, O14843, O15529, O42179, O43603, O46685, O60755, O77408, O88410, O88626, O88634, O88853, P21109, P23944, P25024, P25025, P35344, P35383, P35414, P41231, P41232, P46092, P46093, P49652, P49682, P49683, P50132, P51675, P51679

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
APLNR	“up-regulates activity”	GNAI1	binding
APLNR	“up-regulates activity”	GNAI3	binding
APLNR	“up-regulates activity”	GNA14	binding
Apelin	“up-regulates activity”	APLNR	“chemical activation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

73 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	65
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3338459	GRCh37/hg19 11q12.1(chr11:57003258-57596656)x3	Likely pathogenic
4279315	GRCh37/hg19 11p11.12-q12.2(chr11:51183549-61422182)x3	Likely pathogenic

SpliceAI

215 predictions. Top by Δscore:

Variant	Effect	Δscore
11:57233857:CT:C	acceptor_gain	0.8500
11:57236111:G:C	donor_gain	0.8400
11:57233840:C:G	acceptor_gain	0.7900
11:57236332:C:CT	acceptor_gain	0.7200
11:57233835:CAGCT:C	acceptor_gain	0.7100
11:57234038:C:G	acceptor_gain	0.7000
11:57233859:C:CC	acceptor_gain	0.6800
11:57236466:TG:T	donor_gain	0.6500
11:57234229:C:T	donor_gain	0.6300
11:57236327:T:TC	acceptor_gain	0.6100
11:57234238:G:A	donor_gain	0.5700
11:57236327:T:C	acceptor_gain	0.5400
11:57233854:TGACT:T	acceptor_gain	0.5300
11:57233840:C:CC	acceptor_gain	0.5100
11:57233849:G:GA	acceptor_gain	0.5000
11:57234234:C:T	donor_gain	0.5000
11:57234233:CCCG:C	donor_gain	0.4900
11:57235788:C:CT	donor_gain	0.4700
11:57235789:T:TT	donor_gain	0.4700
11:57233839:T:TG	acceptor_gain	0.4600
11:57233855:GACT:G	acceptor_gain	0.4600
11:57236317:C:CT	acceptor_gain	0.4600
11:57236333:G:T	acceptor_gain	0.4600
11:57235014:T:TA	donor_gain	0.4500
11:57236318:A:T	acceptor_gain	0.4500
11:57234991:A:AC	donor_gain	0.4400
11:57234992:C:CC	donor_gain	0.4400
11:57236242:C:CT	donor_gain	0.4400
11:57233845:C:G	acceptor_gain	0.4300
11:57233856:ACTC:A	acceptor_loss	0.4300

AlphaMissense

2497 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:57236781:T:G	D75A	1.000
11:57236099:G:C	S302R	0.999
11:57236099:G:T	S302R	0.999
11:57236101:T:G	S302R	0.999
11:57236234:A:C	F257L	0.999
11:57236234:A:T	F257L	0.999
11:57236236:A:G	F257L	0.999
11:57236463:C:G	C181S	0.999
11:57236464:A:G	C181R	0.999
11:57236464:A:T	C181S	0.999
11:57236633:G:C	S124R	0.999
11:57236633:G:T	S124R	0.999
11:57236635:T:G	S124R	0.999
11:57236699:G:C	C102W	0.999
11:57236700:C:G	C102S	0.999
11:57236700:C:T	C102Y	0.999
11:57236701:A:T	C102S	0.999
11:57236720:C:A	W95C	0.999
11:57236720:C:G	W95C	0.999
11:57236722:A:G	W95R	0.999
11:57236722:A:T	W95R	0.999
11:57236780:G:C	D75E	0.999
11:57236780:G:T	D75E	0.999
11:57236781:T:A	D75V	0.999
11:57236781:T:C	D75G	0.999
11:57236782:C:G	D75H	0.999
11:57236867:G:C	N46K	0.999
11:57236867:G:T	N46K	0.999
11:57236881:C:G	G42R	0.999
11:57236088:G:A	P306L	0.998

dbSNP variants (sampled 300 via entrez): RS1000024506 (11:57233942 G>A), RS1000546107 (11:57233680 A>C), RS1000614668 (11:57236379 C>A), RS1002101080 (11:57234979 A>C), RS1002383000 (11:57237132 C>T), RS1003344965 (11:57235990 T>A), RS1004520299 (11:57235703 G>A,C), RS1005018909 (11:57234525 G>A), RS1005193335 (11:57233099 G>A,C), RS1005685932 (11:57236466 T>C), RS1006282172 (11:57238105 G>A), RS1006525143 (11:57234251 T>C,G), RS1006665177 (11:57237476 C>T), RS1006737045 (11:57237679 A>T), RS1007074839 (11:57234004 T>G)

Disease associations

OMIM: gene MIM:600052 | disease phenotypes: MIM:615803

GenCC curated gene-disease

Mondo (1): pontocerebellar hypoplasia type 10 (MONDO:0014349)

Orphanet (1): Pontocerebellar hypoplasia type 10 (Orphanet:411493)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1628481 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

9 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 49,982 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1200517	DIHYDROERGOTAMINE MESYLATE	4	2,704
CHEMBL1201082	FLUOXETINE HYDROCHLORIDE	4	18,871
CHEMBL2111101	PIMAVANSERIN	4	1,357
CHEMBL502182	ELAGOLIX SODIUM	4	214
CHEMBL567	PERPHENAZINE	4	21,883
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL405355	NIGULDIPINE	2	1,802
CHEMBL4866732	AZELAPRAG	1	45
CHEMBL4873876	BMS-986224	1	10

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Apelin receptor

Most potent curated ligand interactions (31 total), top 25:

Ligand	Action	Affinity	Parameter
[125I][Nle75,Tyr77]apelin-36 (human)	Full agonist	11.2	pKd
[125I][Glp65Nle75,Tyr77]apelin-13	Full agonist	10.7	pKd
BMS-986224	Agonist	10.52	pKd
compound 21 [PMID: 34855405]	Agonist	10.22	pEC50
compound 15a	Agonist	10.03	pEC50
CMF-019	Biased agonist	10.0	pEC50
compound 14a [PMID: 34795866]	Agonist	9.57	pEC50
125Iapelin-13	Full agonist	9.5	pKd
apelin-13	Full agonist	9.5	pIC50
MM07	Biased agonist	9.5	pEC50
azelaprag	Agonist	9.49	pEC50
apelin receptor early endogenous ligand	Agonist	9.29	pKd
compound 39 [PMID: 34982553]	Agonist	9.22	pKi
[125I]apelin-13	Full agonist	9.2	pKd
apelin-17	Agonist	9.0	pIC50
[Pyr1]apelin-13	Full agonist	8.8	pIC50
Elabela/Toddler-32	Agonist	8.7	pIC50
Elabela/Toddler-21	Agonist	8.7	pIC50
apelin-36	Full agonist	8.6	pIC50
3H[Met(0)11]-apelin-13	Full agonist	8.6	pKd
compound 40 [PMID: 34982553]	Agonist	8.24	pKi
MM54	Antagonist	8.2	pKi
compound 1 [PMID: 25241924]	Full agonist	7.5	pEC50
Elabela/Toddler-11	Agonist	7.2	pIC50
cyclo apelin-12 (7-12)	Full agonist	7.1	pEC50

Binding affinities (BindingDB)

1542 measured of 1712 human assays (1731 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(1R,2S,P)—N-(4-(2,4-dimethoxy-3-pyridinyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide and (1R,2S,M)-N-(4-(2,4-dimethoxy-3-pyridinyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-y0-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide	EC50	0.032 nM	US-10058550: Methods of treating heart failure
(2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(6-ethoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide	EC50	0.062 nM	US-10058550: Methods of treating heart failure
(1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(6-ethoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide	EC50	0.065 nM	US-10058550: Methods of treating heart failure
(2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(6-ethoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide	EC50	0.068 nM	US-10058550: Methods of treating heart failure
(2R)-2-(4-cyano-2-(methylsulfonyl)phenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-2-methoxyethanesulfonamide or (2S)-2-(4-cyano-2-(methylsulfonyl)phenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-2-methoxyethanesulfonamide	EC50	0.073 nM	US-10058550: Methods of treating heart failure
(1S,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, (1R,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide	EC50	0.078 nM	US-10058550: Methods of treating heart failure
(1S,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-ethoxypropane-2-sulfonamide or (1S,2R)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-ethoxypropane-2-sulfonamide or (1R,2R)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-ethoxypropane-2-sulfonamide	EC50	0.082 nM	US-10058550: Methods of treating heart failure
(1S,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, (1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide	EC50	0.09 nM	US-10058550: Methods of treating heart failure
(1S,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-	EC50	0.09 nM	US-10221162: Triazole agonists of the APJ receptor
(2R,3S)-3-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide, (2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide	EC50	0.091 nM	US-10058550: Methods of treating heart failure
(1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-1-methoxy-2-propanesulfonamide	EC50	0.092 nM	US-10058550: Methods of treating heart failure
(1S,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1S,2R)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide or (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide	EC50	0.093 nM	US-10058550: Methods of treating heart failure
(2R,3S)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide, (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide	EC50	0.095 nM	US-10058550: Methods of treating heart failure
(1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)-1-(3-methoxyazetidin-1-yl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide or (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)-1-(3-methoxyazetidin-1-yl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide	EC50	0.095 nM	US-10058550: Methods of treating heart failure
(1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-	EC50	0.095 nM	US-9845310: Intermediates for preparing triazole agonists of the APJ receptor
(1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-	EC50	0.095 nM	US-10221162: Triazole agonists of the APJ receptor
(2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide	EC50	0.1 nM	US-10058550: Methods of treating heart failure
(1S,2S)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide	EC50	0.1 nM	US-10058550: Methods of treating heart failure
(1S,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(1-methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide	EC50	0.11 nM	US-10058550: Methods of treating heart failure
(1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-(2-hydroxyethoxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide or (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-(2-hydroxyethoxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide	EC50	0.11 nM	US-10058550: Methods of treating heart failure
(1S,2S)-1-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(3R)-oxolan-3-yl]-1,2,4-triazol-3-yl]-1-propan-2-yloxypropane-2-sulfonamide	EC50	0.11 nM	US-10150760: Compounds for use in preparing heterocyclic triazole agonists of the APJ receptor
(2S)-N-(4-(2,6-dimethoxyphenyl)-5-(6-ethoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide, (2R)-N-(4-(2,6-dimethoxyphenyl)-5-(6-ethoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide	EC50	0.12 nM	US-10058550: Methods of treating heart failure
(2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-4-methyl-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide	EC50	0.12 nM	US-10058550: Methods of treating heart failure
(2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-4-methyl-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide	EC50	0.12 nM	US-10058550: Methods of treating heart failure
(2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(6-(2,2,2-trifluoroethoxy)-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide	EC50	0.12 nM	US-10058550: Methods of treating heart failure
(2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(6-(2-hydroxyethoxy)-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide	EC50	0.12 nM	US-10058550: Methods of treating heart failure
(R)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-2-methoxyethanesulfonamide and (S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-2-methoxyethanesulfonamide	EC50	0.12 nM	US-9845310: Intermediates for preparing triazole agonists of the APJ receptor
(R)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-2-methoxyethanesulfonamide or (S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-2-methoxyethanesulfonamide	EC50	0.12 nM	US-10058550: Methods of treating heart failure
(1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)-1-(2-methoxyethoxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide	EC50	0.12 nM	US-10058550: Methods of treating heart failure
(2R)-N-[4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-1,2,4-triazol-3-yl]-2-(4-fluoro-2-methylsulfonylphenyl)-2-methoxyethanesulfonamide	EC50	0.12 nM	US-10221162: Triazole agonists of the APJ receptor
(2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide, (2R,3S)-3-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide	EC50	0.13 nM	US-10058550: Methods of treating heart failure
(2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-	EC50	0.13 nM	US-10221162: Triazole agonists of the APJ receptor
(1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(6-([2H3]methoxy)-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide	EC50	0.14 nM	US-10058550: Methods of treating heart failure
(1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(6-(2,2,2-trifluoroethoxy)-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide	EC50	0.14 nM	US-10058550: Methods of treating heart failure
(2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(6-(methylamino)-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-fluoro-2-pyrimidinyl)-2-butanesulfonamide	EC50	0.14 nM	US-10058550: Methods of treating heart failure
(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R,5R)-5-methyloxolan-2-yl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide	EC50	0.14 nM	US-10150760: Compounds for use in preparing heterocyclic triazole agonists of the APJ receptor
(2R)-N-[4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-1,2,4-triazol-3-yl]-2-(4-fluoro-2-methylsulfonylphenyl)-2-methoxy-N-(2-trimethylsilylethyl)ethanesulfonamide	EC50	0.14 nM	US-10221162: Triazole agonists of the APJ receptor
Preparation of (R)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-2-methoxyethanesulfonamide and (S)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-2-methoxyethanesulfonamide	EC50	0.14 nM	US-9845310: Intermediates for preparing triazole agonists of the APJ receptor
(2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(6-ethyl-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide	EC50	0.15 nM	US-10058550: Methods of treating heart failure
(R)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-2-hydroxyethanesulfonamide and (S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-2-hydroxyethanesulfonamide	EC50	0.15 nM	US-10058550: Methods of treating heart failure
(1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)-1-methoxypropane-2-sulfonamide or (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)-1-(5-fluoropyrimidin-2-yl)-1-methoxypropane-2-sulfonamide	EC50	0.15 nM	US-10058550: Methods of treating heart failure
(1S,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(1-methylethoxy)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide, (1R,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(1-methylethoxy)-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide	EC50	0.15 nM	US-10058550: Methods of treating heart failure
(1S,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-	EC50	0.15 nM	US-10221162: Triazole agonists of the APJ receptor
(2R)-2-(4-chloro-2-(methylsulfonyl)phenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide or (2S)-2-(4-chloro-2-(methylsulfonyl)phenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-2-hydroxyethanesulfonamide	EC50	0.16 nM	US-10058550: Methods of treating heart failure
(1R,2S)-1-(2,4-dicyanophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or (1S,2R)-1-(2,4-dicyanophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide	EC50	0.16 nM	US-10058550: Methods of treating heart failure
(1R,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)-1-(3-methoxyazetidin-1-yl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide or (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)-1-(3-methoxyazetidin-1-yl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide	EC50	0.16 nM	US-10058550: Methods of treating heart failure
(2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-difluorophenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide	EC50	0.16 nM	US-10058550: Methods of treating heart failure
(1R,2S)-1-(5-chloropyrimidin-2-yl)-N-[4-(2,6-dimethoxyphenyl)-5-[(2R)-5,5-dimethyloxolan-2-yl]-1,2,4-triazol-3-yl]-1-methoxypropane-2-sulfonamide	EC50	0.16 nM	US-10150760: Compounds for use in preparing heterocyclic triazole agonists of the APJ receptor
(1R,2R)-N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-	EC50	0.16 nM	US-10221162: Triazole agonists of the APJ receptor
(1S,2S)-N-[4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-1,2,4-triazol-3-yl]-1-(3-methoxyazetidin-1-yl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide	EC50	0.16 nM	US-9845310: Intermediates for preparing triazole agonists of the APJ receptor

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	EC50	0.01	nM	CHEMBL4851100
11.00	EC50	0.01	nM	CHEMBL4878056
10.91	EC50	0.0122	nM	CHEMBL3184840
10.80	Ki	0.016	nM	CHEMBL3417384
10.70	IC50	0.02	nM	CHEMBL3417384
10.70	Ki	0.02	nM	CHEMBL4878158
10.70	EC50	0.02	nM	CHEMBL4872345
10.70	EC50	0.02	nM	CHEMBL4864542
10.70	EC50	0.02	nM	CHEMBL5205562
10.70	EC50	0.02	nM	CHEMBL5192130
10.70	EC50	0.02	nM	CHEMBL5208127
10.70	EC50	0.02	nM	CHEMBL5173464
10.70	EC50	0.02	nM	CHEMBL5193130
10.70	EC50	0.02	nM	CHEMBL5202635
10.64	EC50	0.023	nM	BMS-986224
10.64	EC50	0.023	nM	CHEMBL4861895
10.57	EC50	0.027	nM	CHEMBL4854412
10.52	EC50	0.03	nM	CHEMBL4872583
10.52	EC50	0.03	nM	CHEMBL4848436
10.52	EC50	0.03	nM	CHEMBL4872192
10.52	EC50	0.03	nM	CHEMBL5202233
10.52	EC50	0.03	nM	CHEMBL5175424
10.49	EC50	0.032	nM	CHEMBL4867145
10.49	EC50	0.032	nM	CHEMBL5838286
10.40	Ki	0.04	nM	CHEMBL3234446
10.40	EC50	0.04	nM	CHEMBL3417385
10.40	Ki	0.04	nM	CHEMBL4876632
10.40	EC50	0.04	nM	CHEMBL4873216
10.40	EC50	0.04	nM	CHEMBL4863554
10.40	EC50	0.04	nM	CHEMBL5197398
10.33	EC50	0.047	nM	CHEMBL3184840
10.30	EC50	0.05	nM	CHEMBL4850818
10.30	EC50	0.05	nM	CHEMBL4855918
10.30	EC50	0.05	nM	CHEMBL3184840
10.30	EC50	0.05	nM	CHEMBL414173
10.30	EC50	0.05	nM	CHEMBL5854669
10.25	EC50	0.056	nM	CHEMBL6059481
10.22	EC50	0.06	nM	CHEMBL5170657
10.22	EC50	0.06	nM	CHEMBL5923404
10.21	EC50	0.062	nM	CHEMBL4473347
10.21	EC50	0.062	nM	CHEMBL5960144
10.21	EC50	0.061	nM	CHEMBL5926352
10.19	EC50	0.065	nM	CHEMBL5941121
10.19	EC50	0.064	nM	CHEMBL6027440
10.17	EC50	0.068	nM	CHEMBL5907181
10.15	EC50	0.07	nM	CHEMBL3417389
10.15	EC50	0.07	nM	CHEMBL4639193
10.15	Ki	0.07	nM	CHEMBL4867453
10.15	EC50	0.07	nM	CHEMBL5179504
10.15	Ki	0.07	nM	CHEMBL5170657

PubChem BioAssay actives

1088 with measured affinity, of 1707 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-1-[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-1-[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-5-oxopyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]hexanoyl]amino]acetyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(4-phenylmethoxyphenyl)propanoic acid	1200200: Displacement of [125I]apelin-13[Glp65,Nle75,Tyr77] from YFP epitope-tagged human APJ receptor expressed in HEK293 cell membranes incubated for 1 hr by gamma counting method	ic50	<0.0001	uM
(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-1-[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-1-[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-5-oxopyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]hexanoyl]amino]acetyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(4-benzoylphenyl)propanoic acid	1200202: Agonist activity at human APJ receptor expressed in HEK293 cells assessed as inhibition of forskolin-induced intracellular cAMP production incubated for 30 mins by TR-FRET assay	ec50	<0.0001	uM
6-butyl-3-[4-(5-chloro-2-oxo-1-pyridinyl)phenyl]sulfonyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one	1752297: Agonist activity at human APJ receptor assessed as effect on cAMP accumulation by cAMP-Glo assay	ec50	<0.0001	uM
3-[5-[(5-chloro-2-pyridinyl)methyl]-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-4-hydroxy-1H-pyridin-2-one	1752297: Agonist activity at human APJ receptor assessed as effect on cAMP accumulation by cAMP-Glo assay	ec50	<0.0001	uM
5-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-3-(2,6-dimethoxyphenyl)-6-hydroxy-2-(1-methylpyrazol-4-yl)pyrimidin-4-one	1847790: Agonist activity at human APJ expressed in HEK293 cells assessed as inhibition of forskolin-stimulated cAMP production incubated for 60 mins by fluorescence based analysis	ec50	<0.0001	uM
5-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-3-(2,6-dimethoxyphenyl)-6-hydroxy-2-(2-methyl-1,3-thiazol-4-yl)pyrimidin-4-one	1847790: Agonist activity at human APJ expressed in HEK293 cells assessed as inhibition of forskolin-stimulated cAMP production incubated for 60 mins by fluorescence based analysis	ec50	<0.0001	uM
3-(2,6-diethylphenyl)-5-[3-(3-fluoro-2-pyridinyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methylpyrazol-3-yl)pyrimidin-4-one	1847790: Agonist activity at human APJ expressed in HEK293 cells assessed as inhibition of forskolin-stimulated cAMP production incubated for 60 mins by fluorescence based analysis	ec50	<0.0001	uM
3-(2,6-diethylphenyl)-5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methylpyrazol-3-yl)pyrimidin-4-one	1847790: Agonist activity at human APJ expressed in HEK293 cells assessed as inhibition of forskolin-stimulated cAMP production incubated for 60 mins by fluorescence based analysis	ec50	<0.0001	uM
5-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-3-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxypyrimidin-4-one	1847790: Agonist activity at human APJ expressed in HEK293 cells assessed as inhibition of forskolin-stimulated cAMP production incubated for 60 mins by fluorescence based analysis	ec50	<0.0001	uM
5-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-3-(2,6-dimethoxyphenyl)-6-hydroxy-2-(1-methylpyrazol-3-yl)pyrimidin-4-one	1847790: Agonist activity at human APJ expressed in HEK293 cells assessed as inhibition of forskolin-stimulated cAMP production incubated for 60 mins by fluorescence based analysis	ec50	<0.0001	uM
2-butyl-5-(4-cyclopropylphenyl)sulfonyl-3-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4-one	1752297: Agonist activity at human APJ receptor assessed as effect on cAMP accumulation by cAMP-Glo assay	ec50	<0.0001	uM
2-butyl-3-(2,6-dimethoxyphenyl)-5-[4-(6-fluoro-3-pyridinyl)phenyl]sulfonyl-6-hydroxypyrimidin-4-one	1752297: Agonist activity at human APJ receptor assessed as effect on cAMP accumulation by cAMP-Glo assay	ec50	<0.0001	uM
2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-[4-(2-methoxy-3-pyridinyl)phenyl]sulfonylpyrimidin-4-one	1752297: Agonist activity at human APJ receptor assessed as effect on cAMP accumulation by cAMP-Glo assay	ec50	<0.0001	uM
2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-[4-(2-oxo-1-pyridinyl)phenyl]sulfonylpyrimidin-4-one	1752297: Agonist activity at human APJ receptor assessed as effect on cAMP accumulation by cAMP-Glo assay	ec50	<0.0001	uM
3-(2,6-dimethoxyphenyl)-5-[4-(6-fluoro-3-pyridinyl)phenyl]sulfonyl-6-hydroxy-2-(propan-2-yloxymethyl)pyrimidin-4-one	1752297: Agonist activity at human APJ receptor assessed as effect on cAMP accumulation by cAMP-Glo assay	ec50	<0.0001	uM
N-[4-[4-[2-butyl-1-(2,6-dimethoxyphenyl)-4-hydroxy-6-oxopyrimidin-5-yl]sulfonylphenyl]-2-pyridinyl]cyclopropanecarboxamide	1752297: Agonist activity at human APJ receptor assessed as effect on cAMP accumulation by cAMP-Glo assay	ec50	<0.0001	uM
6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-[4-(3-methyl-4-pyridinyl)phenyl]sulfonyl-1H-pyridin-2-one	1752297: Agonist activity at human APJ receptor assessed as effect on cAMP accumulation by cAMP-Glo assay	ec50	<0.0001	uM
6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-[4-(2-methoxy-3-pyridinyl)phenyl]sulfonyl-1H-pyridin-2-one	1752297: Agonist activity at human APJ receptor assessed as effect on cAMP accumulation by cAMP-Glo assay	ec50	<0.0001	uM
(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-1-[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-carbamimidamido-2-[[(2S)-5-carbamimidamido-2-[[(2S)-2-[[(2S)-2,6-diaminohexanoyl]amino]-3-phenylpropanoyl]amino]pentanoyl]amino]pentanoyl]amino]-5-oxopentanoyl]amino]-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]hexanoyl]amino]acetyl]pyrrolidine-2-carbonyl]amino]-4-methylsulfanylbutanoyl]pyrrolidine-2-carbonyl]amino]-3-phenylpropanoic acid	1130006: Displacement of [125I]-pE13F from human apelin receptor expressed in CHO cell membranes after 1 hr by gamma counting analysis	ki	<0.0001	uM
2-butyl-5-[(3R)-3-(5-chloro-2-pyridinyl)pyrrolidine-1-carbonyl]-3-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4-one	1780660: Agonist activity at human APJ receptor expressed in HEK293T cells assessed as compound stimulated inhibition of forskolin stimulated cAMP production incubated for 30 mins by HTRF assay	ec50	<0.0001	uM
5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-4-hydroxy-3-[5-[(5-methyl-2-pyridinyl)methyl]-1,3,4-oxadiazol-2-yl]-1H-pyridin-2-one	1780660: Agonist activity at human APJ receptor expressed in HEK293T cells assessed as compound stimulated inhibition of forskolin stimulated cAMP production incubated for 30 mins by HTRF assay	ec50	<0.0001	uM
2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-(4-pyridin-3-ylphenyl)sulfonylpyrimidin-4-one	1752297: Agonist activity at human APJ receptor assessed as effect on cAMP accumulation by cAMP-Glo assay	ec50	<0.0001	uM
2-butyl-5-[(3S)-3-(5-chloro-2-pyridinyl)pyrrolidine-1-carbonyl]-3-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4-one	1780660: Agonist activity at human APJ receptor expressed in HEK293T cells assessed as compound stimulated inhibition of forskolin stimulated cAMP production incubated for 30 mins by HTRF assay	ec50	<0.0001	uM
2-[[(2S)-1-[(2S)-2-[[(2S)-1-[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-1-[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-5-oxopyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]hexanoyl]amino]acetyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-2-benzyl-3-phenylpropanoic acid	1749755: Displacement of [125I] [NIe75,Tyr77]Pyr-apelin-13 from YFP-tagged human APJ receptor expressed in HEK293 cells incubated for 1 hr by gamma counting analysis	ki	<0.0001	uM
(2R)-2-[[(2S)-1-[(2S)-2-[[(2S)-1-[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-1-[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-5-oxopyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]hexanoyl]amino]acetyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(4-phenylmethoxyphenyl)propanoic acid	1749755: Displacement of [125I] [NIe75,Tyr77]Pyr-apelin-13 from YFP-tagged human APJ receptor expressed in HEK293 cells incubated for 1 hr by gamma counting analysis	ki	<0.0001	uM
3-(2,6-dimethoxyphenyl)-5-[(3R)-3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methylpyrazol-3-yl)pyrimidin-4-one	1847790: Agonist activity at human APJ expressed in HEK293 cells assessed as inhibition of forskolin-stimulated cAMP production incubated for 60 mins by fluorescence based analysis	ec50	<0.0001	uM
3-(2,6-diethylphenyl)-5-[(3R)-3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methylpyrazol-3-yl)pyrimidin-4-one	1847790: Agonist activity at human APJ expressed in HEK293 cells assessed as inhibition of forskolin-stimulated cAMP production incubated for 60 mins by fluorescence based analysis	ec50	<0.0001	uM
3-(2,6-diethylphenyl)-5-[(3R)-3-(3,5-difluoro-2-pyridinyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methylpyrazol-3-yl)pyrimidin-4-one	1847790: Agonist activity at human APJ expressed in HEK293 cells assessed as inhibition of forskolin-stimulated cAMP production incubated for 60 mins by fluorescence based analysis	ec50	<0.0001	uM
(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-1-[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-1-[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-5-oxopyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]hexanoyl]amino]acetyl]pyrrolidine-2-carbonyl]amino]-4-methylsulfanylbutanoyl]pyrrolidine-2-carbonyl]amino]-3-phenylpropanoic acid	1165184: Agonist activity at APJ receptor in HEK293 cells assessed as inhibition of forskolin-induced cAMP level incubated for 5 mins prior to forskolin challenge measured after 30 mins by TR-FRET assay	ec50	<0.0001	uM
(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-1-[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-1-[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-5-oxopyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]hexanoyl]amino]acetyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-2-methyl-3-phenylpropanoic acid	1200202: Agonist activity at human APJ receptor expressed in HEK293 cells assessed as inhibition of forskolin-induced intracellular cAMP production incubated for 30 mins by TR-FRET assay	ec50	0.0001	uM
(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-1-[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-1-[(2S)-5-(diaminomethylideneamino)-2-[(5-oxopyrrolidine-2-carbonyl)amino]pentanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]hexanoyl]amino]acetyl]pyrrolidine-2-carbonyl]amino]-4-methylsulfanylbutanoyl]pyrrolidine-2-carbonyl]amino]-3-phenylpropanoic acid	1573484: Agonist activity at human APJ receptor by saphenous vein contraction assay	ec50	0.0001	uM
3-[5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-4-hydroxy-1H-pyridin-2-one	1762005: Agonist activity at human APJ receptor expressed in human HEK293 cells assessed as inhibition of forskolin-induced cAMP accumulation incubated for 1 hr by TR-FRET assay	ec50	0.0001	uM
2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-pyridin-2-ylpyrrolidine-1-carbonyl)pyrimidin-4-one	1780660: Agonist activity at human APJ receptor expressed in HEK293T cells assessed as compound stimulated inhibition of forskolin stimulated cAMP production incubated for 30 mins by HTRF assay	ec50	0.0001	uM
2-butyl-5-[3-(4-chlorophenyl)pyrrolidine-1-carbonyl]-3-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4-one	1780660: Agonist activity at human APJ receptor expressed in HEK293T cells assessed as compound stimulated inhibition of forskolin stimulated cAMP production incubated for 30 mins by HTRF assay	ec50	0.0001	uM
2-butyl-3-(2,6-dimethoxyphenyl)-5-[4-(4-fluorophenyl)phenyl]sulfonyl-6-hydroxypyrimidin-4-one	1752297: Agonist activity at human APJ receptor assessed as effect on cAMP accumulation by cAMP-Glo assay	ec50	0.0001	uM
2-butyl-5-[4-(5-chloro-2-oxo-1-pyridinyl)phenyl]sulfonyl-3-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4-one	1752297: Agonist activity at human APJ receptor assessed as effect on cAMP accumulation by cAMP-Glo assay	ec50	0.0001	uM
2-[2-(1H-benzimidazol-2-yl)-6-chlorophenyl]-5-[[(1R)-1-phenylbutyl]carbamoyl]benzoic acid	1527816: Agonist activity at human APJ-R expressed in HEK293 cells assessed as inhibition of forskolin- stimulated cAMP accumulation incubated for 30 mins by HTRF assay	ec50	0.0001	uM
2-[5-chloro-2-(6-methoxy-1H-benzimidazol-2-yl)phenyl]-5-[[(1R)-1-phenylbutyl]carbamoyl]benzoic acid	1527816: Agonist activity at human APJ-R expressed in HEK293 cells assessed as inhibition of forskolin- stimulated cAMP accumulation incubated for 30 mins by HTRF assay	ec50	0.0001	uM
(3S,6S,12S,17Z,20R,23S)-12-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-1-[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-5-oxopyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]hexanoyl]amino]-3-butyl-15-(2-nitrophenyl)sulfonyl-2,5,11,22-tetraoxo-1,4,10,15,21-pentazatricyclo[21.3.0.06,10]hexacos-17-ene-20-carboxylic acid	1468977: Displacement of [125I]-[Nle75, Tyr77] Pyr1-apelin-13 from YFP-tagged human APJ receptor expressed in HEK293 cell membranes after 1 hr by gamma-counting method	ki	0.0001	uM
(3S,6S,12S,17Z,20S,23S)-12-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-1-[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-5-oxopyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]hexanoyl]amino]-3-butyl-15-(2-nitrophenyl)sulfonyl-2,5,11,22-tetraoxo-1,4,10,15,21-pentazatricyclo[21.3.0.06,10]hexacos-17-ene-20-carboxylic acid	1468977: Displacement of [125I]-[Nle75, Tyr77] Pyr1-apelin-13 from YFP-tagged human APJ receptor expressed in HEK293 cell membranes after 1 hr by gamma-counting method	ki	0.0001	uM
3-(2,6-dimethoxyphenyl)-5-[4-(6-fluoro-3-pyridinyl)phenyl]sulfonyl-6-hydroxy-2-(3-methylbutyl)pyrimidin-4-one	1752297: Agonist activity at human APJ receptor assessed as effect on cAMP accumulation by cAMP-Glo assay	ec50	0.0001	uM
3-[3-(3,5-difluoro-2-pyridinyl)pyrrolidine-1-carbonyl]-5-(N-ethylanilino)-4-hydroxy-6-(3-methylphenyl)-1H-pyridin-2-one	1850911: Agonist activity at human APJ receptor expressed in HEK293 cells assessed as compound stimulated inhibition of forskolin stimulated cAMP production incubated for 30 mins and measured by fluorescence based assay	ec50	0.0001	uM
5-[(3R)-3-(5-chloro-3-fluoro-2-pyridinyl)pyrrolidine-1-carbonyl]-3-(2,6-diethylphenyl)-6-hydroxy-2-(1-methylpyrazol-3-yl)pyrimidin-4-one	1847790: Agonist activity at human APJ expressed in HEK293 cells assessed as inhibition of forskolin-stimulated cAMP production incubated for 60 mins by fluorescence based analysis	ec50	0.0001	uM
(2R)-1-[(2R)-2-[[(2R)-1-[(2R)-2-[[(2R)-5-(diaminomethylideneamino)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-[[(2R)-1-[(2R)-2-[[(2S)-2-[[(2R)-5-(diaminomethylideneamino)-2-[[(2S)-5-(diaminomethylideneamino)-2-[(5-oxopyrrolidine-2-carbonyl)amino]pentanoyl]amino]pentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]pyrrolidine-2-carbonyl]amino]-4-methylpentanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]propanoyl]amino]pentanoyl]amino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]-3-phenylpropanoyl]pyrrolidine-2-carboxylic acid	1301658: Displacement of [125I]-Apelin-13[Glp65, Nle75, Tyr77] from YFP epitope-tagged human APJ expressed in HEK-293 cells after 1 hr by gamma counting method	ki	0.0001	uM
(2R)-1-[(2R)-2-[[(2R)-1-[(2R)-2-[[(2R)-5-(diaminomethylideneamino)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-[[(2R)-1-[2-[[(2S)-2-[[(2R)-5-(diaminomethylideneamino)-2-[[(2S)-5-(diaminomethylideneamino)-2-[(5-oxopyrrolidine-2-carbonyl)amino]pentanoyl]amino]pentanoyl]amino]-3-sulfanylpropanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-4-methylpentanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]pentanoyl]amino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]-3-phenylpropanoyl]pyrrolidine-2-carboxylic acid	1301658: Displacement of [125I]-Apelin-13[Glp65, Nle75, Tyr77] from YFP epitope-tagged human APJ expressed in HEK-293 cells after 1 hr by gamma counting method	ki	0.0001	uM
2-[2-chloro-6-(6-methoxy-1H-benzimidazol-2-yl)phenyl]-5-[[(1R)-1-phenylbutyl]carbamoyl]benzoic acid	1527816: Agonist activity at human APJ-R expressed in HEK293 cells assessed as inhibition of forskolin- stimulated cAMP accumulation incubated for 30 mins by HTRF assay	ec50	0.0001	uM
potassium (3S)-5-methyl-3-[[1-pentan-3-yl-2-(thiophen-2-ylmethyl)benzimidazole-5-carbonyl]amino]hexanoate	1573495: Agonist activity at APJ receptor (unknown origin) assessed as inhibition of forskolin-induced cAMP accumulation	ec50	0.0001	uM
(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-1-[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-1-[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-5-oxooxolane-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]hexanoyl]amino]acetyl]pyrrolidine-2-carbonyl]amino]-4-methylsulfanylbutanoyl]pyrrolidine-2-carbonyl]amino]-3-phenylpropanoic acid	1657021: Agonist activity at human APJ expressed in HEK293 cells assessed as inhibition of forskolin-stimulated cAMP production	ec50	0.0001	uM
(3R)-2-[(2R)-2-[[(2S)-2-[[(2S)-1-[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-carbamimidamido-2-[[(2S)-1-[(2S)-5-carbamimidamido-2-[[(2S)-5-oxopyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]hexanoyl]amino]acetyl]pyrrolidine-2-carbonyl]amino]hexanoyl]amino]-3-naphthalen-1-ylpropanoyl]-3,4-dihydro-1H-isoquinoline-3-carboxylic acid	1749755: Displacement of [125I] [NIe75,Tyr77]Pyr-apelin-13 from YFP-tagged human APJ receptor expressed in HEK293 cells incubated for 1 hr by gamma counting analysis	ki	0.0001	uM
2-[[(2R)-2-[[(2S)-2-[[(2S)-1-[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-carbamimidamido-2-[[(2S)-1-[(2S)-5-carbamimidamido-2-[[(2S)-5-oxopyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]hexanoyl]amino]acetyl]pyrrolidine-2-carbonyl]amino]hexanoyl]amino]-3-naphthalen-1-ylpropanoyl]amino]-2-benzyl-3-phenylpropanoic acid	1749755: Displacement of [125I] [NIe75,Tyr77]Pyr-apelin-13 from YFP-tagged human APJ receptor expressed in HEK293 cells incubated for 1 hr by gamma counting analysis	ki	0.0001	uM

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, affects methylation	2
Nickel	decreases expression	2
Valproic Acid	increases expression, increases methylation	2
CGP 52608	affects binding, increases reaction	1
bisphenol S	decreases methylation	1
Decitabine	affects expression	1
Carmustine	decreases expression	1
Cisplatin	affects expression	1
Cytarabine	decreases expression	1
Niclosamide	decreases expression	1
Triclosan	decreases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Endocannabinoids	affects binding, increases activity, increases reaction	1

ChEMBL screening assays

139 unique, capped per target: 70 binding, 65 functional, 2 admet, 2 unclassified

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1794368	Functional	PUBCHEM_BIOASSAY: SAR analysis counterscreen of small molecule antagonists of the CCR6 receptor using an APJ receptor luminescent beta-arrestin assay. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID493098, AID	PubChem BioAssay data set
CHEMBL3242425	Binding	Displacement of [125I]-pE13F from human apelin receptor expressed in CHO cell membranes after 1 hr by gamma counting analysis	Structure-activity relationship studies toward the discovery of selective apelin receptor agonists. — J Med Chem
CHEMBL4627569	ADMET	Agonist activity at human APJ receptor stably expressed in CHOK1 cells assessed as induction of beta-arrestin 2 recruitment incubated for 90 mins by PathHunter assay	Identification of potent pyrazole based APELIN receptor (APJ) agonists. — Bioorg Med Chem

Cellosaurus cell lines

10 cell lines: 5 cancer cell line, 4 spontaneously immortalized cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1R19	NP-2/APJ	Cancer cell line	Male
CVCL_1R25	NP-2/CD4/APJ	Cancer cell line	Male
CVCL_B1JR	Abcam HeLa APLNR KO	Cancer cell line	Female
CVCL_C0S6	ACTOne AGTRL1	Transformed cell line	Female
CVCL_H395	CHO-K1/AGTRL1/Galpha15	Spontaneously immortalized cell line	Female
CVCL_KU80	cAMP Hunter CHO-K1 AGTRL1 Gi	Spontaneously immortalized cell line	Female
CVCL_KW32	PathHunter CHO-K1 AGTRL1 beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_KW33	PathHunter CHO-K1 AGTRL1 beta-arrestin-1	Spontaneously immortalized cell line	Female
CVCL_KZ73	PathHunter U2OS AGTRL1 Activated GPCR Internalization	Cancer cell line	Female
CVCL_ZJ97	Tango AGTRL1-bla U2OS	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.