GUCY1A1

Summary

GUCY1A1 (guanylate cyclase 1 soluble subunit alpha 1, HGNC:4685) is a protein-coding gene on chromosome 4q32.1, encoding Guanylate cyclase soluble subunit alpha-1 (Q02108).

Soluble guanylate cyclases are heterodimeric proteins that catalyze the conversion of GTP to 3’,5’-cyclic GMP and pyrophosphate. The protein encoded by this gene is an alpha subunit of this complex and it interacts with a beta subunit to form the guanylate cyclase enzyme, which is activated by nitric oxide. Several transcript variants encoding a few different isoforms have been found for this gene.

Source: NCBI Gene 2982 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Moyamoya disease with early-onset achalasia (Strong, GenCC)
• GWAS associations: 46
• Clinical variants (ClinVar): 187 total — 13 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 19
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001130682

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4685
Approved symbol	GUCY1A1
Name	guanylate cyclase 1 soluble subunit alpha 1
Location	4q32.1
Locus type	gene with protein product
Status	Approved
Aliases	GC-SA3
Ensembl gene	ENSG00000164116
Ensembl biotype	protein_coding
OMIM	139396
Entrez	2982

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 41 protein_coding, 3 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000296518, ENST00000393832, ENST00000443668, ENST00000455639, ENST00000506455, ENST00000509901, ENST00000511108, ENST00000511507, ENST00000512983, ENST00000513574, ENST00000515201, ENST00000515602, ENST00000621234, ENST00000856255, ENST00000856256, ENST00000856257, ENST00000856258, ENST00000856259, ENST00000856260, ENST00000856261, ENST00000856262, ENST00000856263, ENST00000856264, ENST00000856265, ENST00000856266, ENST00000856267, ENST00000856268, ENST00000856269, ENST00000856270, ENST00000856271, ENST00000856272, ENST00000856273, ENST00000856274, ENST00000856275, ENST00000856276, ENST00000856277, ENST00000856278, ENST00000856279, ENST00000856280, ENST00000856281, ENST00000965163, ENST00000965164, ENST00000965165, ENST00000965166, ENST00000965167, ENST00000965168

RefSeq mRNA: 18 — MANE Select: NM_001130682 NM_000856, NM_001130682, NM_001130683, NM_001130684, NM_001130685, NM_001130687, NM_001256449, NM_001379666, NM_001379667, NM_001379668, NM_001379669, NM_001379670, NM_001379671, NM_001379672, NM_001379673, NM_001379674, NM_001379675, NM_001379676

CCDS: CCDS34085, CCDS54812

Canonical transcript exons

ENST00000506455 — 10 exons

Exon	Start	End
ENSE00002051965	155666848	155666965
ENSE00002526853	155667346	155667419
ENSE00003540521	155703932	155703993
ENSE00003569870	155713098	155713583
ENSE00003588352	155722038	155722192
ENSE00003622306	155696756	155697122
ENSE00003647482	155717159	155717302
ENSE00003658266	155708236	155708294
ENSE00003660035	155710542	155711251
ENSE00003901005	155730030	155737059

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 98.02.

FANTOM5 (CAGE): breadth broad, TPM avg 6.4051 / max 154.2680, expressed in 627 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
50202	2.5707	428
50201	0.8433	288
50210	0.5271	235
50208	0.4679	185
50200	0.3217	166
50212	0.3069	184
50209	0.2256	124
50211	0.2246	139
50203	0.2029	109
50204	0.1960	120

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
urethra	UBERON:0000057	98.02	gold quality
vena cava	UBERON:0004087	97.63	gold quality
saphenous vein	UBERON:0007318	97.28	gold quality
visceral pleura	UBERON:0002401	96.80	gold quality
blood vessel layer	UBERON:0004797	95.99	gold quality
heart right ventricle	UBERON:0002080	95.16	gold quality
myocardium	UBERON:0002349	95.16	gold quality
superficial temporal artery	UBERON:0001614	95.07	gold quality
lower lobe of lung	UBERON:0008949	94.98	gold quality
mammary duct	UBERON:0001765	94.48	gold quality
middle temporal gyrus	UBERON:0002771	94.37	gold quality
epithelium of mammary gland	UBERON:0003244	94.36	gold quality
cardiac muscle of right atrium	UBERON:0003379	94.33	gold quality
renal medulla	UBERON:0000362	94.20	gold quality
left ventricle myocardium	UBERON:0006566	93.71	gold quality
pleura	UBERON:0000977	93.46	gold quality
lateral globus pallidus	UBERON:0002476	93.18	gold quality
pylorus	UBERON:0001166	93.16	gold quality
cardia of stomach	UBERON:0001162	92.92	gold quality
parietal pleura	UBERON:0002400	92.89	gold quality
colonic epithelium	UBERON:0000397	92.82	gold quality
pericardium	UBERON:0002407	92.39	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.33	gold quality
entorhinal cortex	UBERON:0002728	91.29	gold quality
mammary gland	UBERON:0001911	91.15	gold quality
thoracic mammary gland	UBERON:0005200	91.14	gold quality
smooth muscle tissue	UBERON:0001135	90.61	gold quality
right coronary artery	UBERON:0001625	90.46	gold quality
descending thoracic aorta	UBERON:0002345	89.79	gold quality
cortical plate	UBERON:0005343	89.76	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	1122.60
E-CURD-7	yes	230.62
E-MTAB-10287	yes	59.25
E-HCAD-10	yes	47.11
E-MTAB-9067	yes	29.14
E-GEOD-135922	yes	24.93
E-HCAD-11	yes	20.86
E-MTAB-8410	yes	19.78
E-GEOD-137537	yes	15.97
E-ANND-3	yes	14.68
E-CURD-46	yes	9.54
E-GEOD-134144	yes	9.38
E-CURD-112	yes	5.67
E-GEOD-110499	no	634.44

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, AR, SP1

miRNA regulators (miRDB)

276 targeting GUCY1A1, 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-3646	100.00	73.56	5283
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-19A-3P	99.98	75.33	2762

Literature-anchored findings (GeneRIF, showing 30)

• Soluble guanylate cyclases could be the target molecules for controlling neo-vascularization in a subset of human malignant gliomas. (PMID:15201957)
• guanylate cyclase has a role in pulmonary arterial hypertension (PMID:18550612)
• C-alpha1 sGC splice form is expressed at high levels in differentiating cells and its intracellular distribution varies from canonical alpha1 sGC subunit. (PMID:20964618)
• NO, depending on its concentration, may act in human PBMCs as a stimulator of IL-6 expression and modulator of NF-KB involving the sGC/cGMP/PKG pathway (PMID:21414799)
• A novel insight into the heme and NO/CO binding mechanism of the alpha subunit of human soluble guanylate cyclase (PMID:21725643)
• analysis of pharmacological response to direct sGC activators in coronary artery disease patients (PMID:21794866)
• GCS-alpha-1 regulation of p53 activity is important in prostate cancer biology and may represent an important mechanism of p53 down-regulation. (PMID:22174378)
• We concluded that the alpha-subunit and the beta(1)(191-619) domain exert structural strains on the heme domain. (PMID:22223482)
• The G-protein regulator LGN modulates the activity of the NO receptor soluble guanylate cyclase (PMID:22690686)
• ZNF280B upregulates GUCY1A3 expression and downregulates TP53 in prostate cancer cells. (PMID:24236047)
• homozygous mutations in GUCY1A3, which encodes the alpha1 subunit of soluble guanylate cyclase, the major receptor for nitric oxide, might play a role in moyamoya and achalasia (PMID:24581742)
• Dynamic interplay between hsp90, apo-sGC-beta1, and sGC-alpha1 in response to NO is unprecedented and represent new steps by which cells can modulate the heme content and activity of sGC for signaling cascades. (PMID:24733395)
• Expression of the alpha1-A680T sGC variant in reporter cells resulted in higher cyclic guanosine monophosphate production compared with the wild-type enzyme and the purified alpha1-A680T sGC exhibited enhanced sensitivity to nitric oxide in vitro. (PMID:25373139)
• Mutations in the GUCY1A3 gene are associated with moyamoya disease, achalasia, and hypertension. (PMID:26777256)
• In conclusion, rare coding variants in GUCY1A3 lead to reduced cGMP formation which can be rescued by a soluble guanylyl cyclase stimulator in vitro (PMID:27342234)
• GCAP1 and GCAP2 bound to different regions on the target guanylate cyclase type 1 with submicromolar affinity (apparent KD-values of 663 +/- 121 nM and 231 +/- 63 nM for Ca(2+)-free GCAP1 and GCAP2, respectively). (PMID:28361875)
• Rs7692387 is located in an intronic site that modulates GUCY1A3 promoter activity. The transcription factor ZEB1 binds preferentially to the nonrisk allele, leading to an increase in GUCY1A3 expression, higher sGC levels, and higher sGC activity after stimulation. (PMID:28487391)
• Peptide B-8R killed both androgen-dependent and androgen-independent prostate cancer cells that expressed sGCalpha1, but not cells that do not express this gene. Peptide B-8R induced apoptosis of prostate cancer cells. (PMID:28859127)
• Genetic predisposition to enhanced nitric oxide signaling was associated with reduced blood pressure, improved renal and pulmonary function, and significantly reduced risks of coronary heart disease in people with rs7692387 GUCY1A3 variant. (PMID:28982690)
• Human Red Blood Cells carry catalytically active alpha1beta1-soluble guanylate cyclase (isoform 1). Red cell soluble guanylate cyclase activity is fully preserved in patients with stable coronary artery disease. (PMID:29024896)
• data have provided some evidence for an alteration in the expression of alpha1 and beta1 oluble guanylyl cyclase alternative splicing forms which may contribute to the loss of sGC functions in breast cancer (PMID:30597209)
• Homozygous GUCY1A3 risk allele carriers are at increased risk of cardiovascular death or stent thrombosis within 30 days after coronary stenting, likely due to higher on-aspirin platelet reactivity. (PMID:30768153)
• Genetic variation at the coronary artery disease risk locus GUCY1A3 modifies cardiovascular disease prevention effects of aspirin. (PMID:31228190)
• Soluble guanylyl cyclase alpha1 subunit is a key mediator of proliferation, survival, and migration in ECC-1 and HeLa cell lines. (PMID:31616026)
• Results suggest mechanistic insights into the molecular pathway for soluble guanylyl cyclase (sGC) activation. (PMID:31645439)
• Our results indicate that the GUCY1A3 rs1842896 polymorphism is an large artery atherosclerotic (LAA) stroke risk factor in Southern Han Chinese. (PMID:31883534)
• Inflammation in the Human Periodontium Induces Downregulation of the alpha1- and beta1-Subunits of the sGC in Cementoclasts. (PMID:33430449)
• Higher susceptibility to heme oxidation and lower protein stability of the rare alpha1C517Ybeta1 sGC variant associated with moyamoya syndrome. (PMID:33571505)
• Activation mechanism of human soluble guanylate cyclase by stimulators and activators. (PMID:34535643)
• Biallelic variants in NOS3 and GUCY1A3, the two major genes of the nitric oxide pathway, cause moyamoya cerebral angiopathy. (PMID:36941667)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gucy1a1	ENSDARG00000013787
mus_musculus	Gucy1a1	ENSMUSG00000033910
rattus_norvegicus	Gucy1a1	ENSRNOG00000012302

Paralogs (17): GUCY1B1 (ENSG00000061918), GUCY2C (ENSG00000070019), ADCY2 (ENSG00000078295), GUCY2F (ENSG00000101890), NPR3 (ENSG00000113389), ADCY7 (ENSG00000121281), ADCY4 (ENSG00000129467), GUCY2D (ENSG00000132518), ADCY3 (ENSG00000138031), GUCY1A2 (ENSG00000152402), ADCY8 (ENSG00000155897), NPR2 (ENSG00000159899), ADCY9 (ENSG00000162104), ADCY1 (ENSG00000164742), NPR1 (ENSG00000169418), ADCY5 (ENSG00000173175), ADCY6 (ENSG00000174233)

Protein

Protein identifiers

Guanylate cyclase soluble subunit alpha-1 — Q02108 (reviewed: Q02108)

Alternative names: Guanylate cyclase soluble subunit alpha-3, Soluble guanylate cyclase large subunit

All UniProt accessions (5): Q02108, D6RF78, J3KPQ8, J3KQW2, Q6PJR4

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. The active enzyme is formed by a heterodimer of an alpha and a beta subunit. Heterodimer with GUCY1B1.

Subcellular location. Cytoplasm.

Tissue specificity. Detected in brain cortex and lung (at protein level).

Disease relevance. Moyamoya disease 6 with or without achalasia (MYMY6) [MIM:615750] A form of Moyamoya disease, a progressive cerebral angiopathy characterized by bilateral intracranial carotid artery stenosis and telangiectatic vessels in the region of the basal ganglia. The abnormal vessels resemble a ‘puff of smoke’ (moyamoya) on cerebral angiogram. Affected individuals can develop transient ischemic attacks and/or cerebral infarction, and rupture of the collateral vessels can cause intracranial hemorrhage. Hemiplegia of sudden onset and epileptic seizures constitute the prevailing presentation in childhood, while subarachnoid bleeding occurs more frequently in adults. MYMY6 is characterized by severe cerebral angiopathy and onset of severe achalasia in infancy or early childhood. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by nitric oxide in the presence of magnesium or manganese ions.

Cofactor. Also has activity with Mn(2+) (in vitro).

Miscellaneous. There are two types of guanylate cyclases: soluble forms and membrane-associated receptor forms.

Similarity. Belongs to the adenylyl cyclase class-4/guanylyl cyclase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q02108-1	1	yes
Q02108-2	2

RefSeq proteins (18): NP_000847, NP_001124154, NP_001124155, NP_001124156, NP_001124157, NP_001124159, NP_001243378, NP_001366595, NP_001366596, NP_001366597, NP_001366598, NP_001366599, NP_001366600, NP_001366601, NP_001366602, NP_001366603, NP_001366604, NP_001366605 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001054	A/G_cyclase	Domain
IPR011645	HNOB_dom_associated	Domain
IPR018297	A/G_cyclase_CS	Conserved_site
IPR024096	NO_sig/Golgi_transp_ligand-bd	Homologous_superfamily
IPR029787	Nucleotide_cyclase	Homologous_superfamily
IPR038158	H-NOX_domain_sf	Homologous_superfamily
IPR042463	HNOB_dom_associated_sf	Homologous_superfamily

Pfam: PF00211, PF07701

Enzyme classification (BRENDA):

• EC 4.6.1.2 — guanylate cyclase (BRENDA: 58 organisms, 213 substrates, 212 inhibitors, 100 Km, 16 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GTP	0.01–6.09	90
2’-O-(N-METHYLANTHRANILOYL) GUANOSINE 5’-TRIPHOS	0.0357	1
GUANYL-(BETA,GAMMA-METHYLENE)-DIPHOSPHONATE	0.37	1
GUANYL-IMIDODIPHOSPHATE	0.07	1
MN2+	2.7	1

Catalyzed reactions (Rhea), 1 shown:

• GTP = 3’,5’-cyclic GMP + diphosphate (RHEA:13665)

UniProt features (62 total): strand 24, helix 23, turn 5, sequence conflict 5, chain 1, domain 1, modified residue 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
4NI2	X-RAY DIFFRACTION	1.9
3UVJ	X-RAY DIFFRACTION	2.08
8HBF	ELECTRON MICROSCOPY	3.1
8HBH	ELECTRON MICROSCOPY	3.1
8HBE	ELECTRON MICROSCOPY	3.2
7D9R	ELECTRON MICROSCOPY	3.7
6JT2	ELECTRON MICROSCOPY	3.8
7D9U	ELECTRON MICROSCOPY	3.8
6JT1	ELECTRON MICROSCOPY	3.9
7D9S	ELECTRON MICROSCOPY	3.9
6JT0	ELECTRON MICROSCOPY	4
7D9T	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q02108-F1	77.79	0.36

Functional residue map

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

Post-translational modifications (1): 267

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-392154	Nitric oxide stimulates guanylate cyclase
R-HSA-445355	Smooth Muscle Contraction

MSigDB gene sets: 363 (showing top): BENPORATH_ES_WITH_H3K27ME3, chr4q32, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CONTRACTION, GCANCTGNY_MYOD_Q6, GOBP_CGMP_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_SMOOTH_MUSCLE_CONTRACTION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CYCLIC_NUCLEOTIDE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GRAHAM_CML_QUIESCENT_VS_NORMAL_QUIESCENT_DN, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS

GO Biological Process (12): cGMP biosynthetic process (GO:0006182), obsolete nitric oxide mediated signal transduction (GO:0007263), blood circulation (GO:0008015), regulation of blood pressure (GO:0008217), obsolete positive regulation of nitric oxide mediated signal transduction (GO:0010750), obsolete cGMP-mediated signaling (GO:0019934), nitric oxide-cGMP-mediated signaling (GO:0038060), relaxation of vascular associated smooth muscle (GO:0060087), response to oxygen levels (GO:0070482), retrograde trans-synaptic signaling by nitric oxide, modulating synaptic transmission (GO:0098925), cyclic nucleotide biosynthetic process (GO:0009190), intracellular signal transduction (GO:0035556)

GO Molecular Function (8): guanylate cyclase activity (GO:0004383), GTP binding (GO:0005525), heme binding (GO:0020037), signaling receptor activity (GO:0038023), nucleotide binding (GO:0000166), protein binding (GO:0005515), lyase activity (GO:0016829), phosphorus-oxygen lyase activity (GO:0016849)

GO Cellular Component (5): cytosol (GO:0005829), guanylate cyclase complex, soluble (GO:0008074), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Platelet homeostasis	1
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
cellular anatomical structure	2
synapse	2
purine ribonucleotide biosynthetic process	1
cyclic nucleotide biosynthetic process	1
cGMP metabolic process	1
circulatory system process	1
blood circulation	1
regulation of biological quality	1
intracellular signaling cassette	1
vasodilation	1
relaxation of smooth muscle	1
negative regulation of smooth muscle contraction	1
response to abiotic stimulus	1
retrograde trans-synaptic signaling by nitric oxide	1
trans-synaptic signaling by nitric oxide, modulating synaptic transmission	1
nucleotide biosynthetic process	1
cyclic nucleotide metabolic process	1
signal transduction	1
cGMP biosynthetic process	1
cyclase activity	1
phosphorus-oxygen lyase activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
tetrapyrrole binding	1
molecular transducer activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
lyase activity	1
cytoplasm	1
cytosol	1
catalytic complex	1

Protein interactions and networks

STRING

1328 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GUCY1A1	GUCY1B1	Q02153	950
GUCY1A1	GUCY1A2	P33402	660
GUCY1A1	TTC32	Q5I0X7	558
GUCY1A1	DLG4	P78352	549
GUCY1A1	RNF213	Q63HN8	474
GUCY1A1	ZC3HC1	Q86WB0	445
GUCY1A1	APOL1	O14791	439
GUCY1A1	TAFA3	Q7Z5A8	422
GUCY1A1	PDE5A	O76074	421
GUCY1A1	CCT7	Q99832	411
GUCY1A1	PLIN2	Q99541	410
GUCY1A1	IRAG1	Q9Y6F6	408
GUCY1A1	PRKG2	Q13237	402
GUCY1A1	MRPL18	Q9H0U6	396
GUCY1A1	PRKG1	P14619	390

IntAct

10 interactions, top by confidence:

A	B	Type	Score
GUCY1A1	GUCY1B1	psi-mi:“MI:0407”(direct interaction)	0.670
GUCY1A1	GUCY1B1	psi-mi:“MI:0883”(gtpase reaction)	0.670
GUCY1A1	SART1	psi-mi:“MI:0915”(physical association)	0.400
GUCY1A1	MAPK8	psi-mi:“MI:0915”(physical association)	0.370
IKBKG	GUCY1A1	psi-mi:“MI:0915”(physical association)	0.370
ANKMY2	ADCY6	psi-mi:“MI:0914”(association)	0.350
GUCY1B1	MYCBP2	psi-mi:“MI:0914”(association)	0.350
GUCY1A1	SULT2B1	psi-mi:“MI:0914”(association)	0.350

BioGRID (45): COPS4 (Affinity Capture-Western), GUCY1A3 (Affinity Capture-Western), TP53 (Affinity Capture-Western), GUCY1A3 (Affinity Capture-Western), GUCY1A3 (Affinity Capture-Western), COPS5 (Affinity Capture-Western), GUCY1A3 (Affinity Capture-Western), GUCY1A3 (Affinity Capture-MS), GUCY1A3 (Affinity Capture-MS), GUCY1A3 (Affinity Capture-RNA), AGAP1 (Two-hybrid), AGAP1 (Affinity Capture-Western), GUCY1A3 (Proximity Label-MS), TGM3 (Affinity Capture-MS), TYMP (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IMY7, A0JPA0, A2AP18, A8DYE2, J9SQF3, O00329, O35904, O75038, P0C1Q3, P0C588, P19687, P33402, P48736, P97557, Q02108, Q09M05, Q148L1, Q1LWG4, Q2TV84, Q2WEA5, Q3USB7, Q4ZHS0, Q502J0, Q5EBA1, Q60565, Q62688, Q69ZF7, Q6P4Q7, Q6PA06, Q7L5N7, Q7TN37, Q7Z2W7, Q7Z4N2, Q80YD1, Q8BTI9, Q8BYI6, Q8BZN2, Q8CIR4, Q8NHH9, Q8R455

Diamond homologs: A0A078BQP2, A0A0U1RPR8, E7EAU8, H2L002, O02298, O02740, O16715, O19179, O54865, O62179, O75343, P0A4Y1, P16065, P16066, P16068, P18293, P18910, P19686, P19687, P20594, P20595, P22717, P23897, P25092, P26770, P33402, P51840, P51841, P51842, P52785, P55202, P55203, P55204, P70106, P90895, P91550, P92006, P9WQ34, P9WQ35, Q02108

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
GUCY1A1	“form complex”	GUCY1A3-B3	binding
GUCY1A1	“form complex”	GUCY1A3-B2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	2
Uncertain significance	95
Likely benign	35
Benign	12

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
127094	NM_001130682.3(GUCY1A1):c.1086+1G>A	Pathogenic
127095	NM_001130682.3(GUCY1A1):c.1045C>T (p.Arg349Ter)	Pathogenic
127096	NM_001130682.3(GUCY1A1):c.1170del (p.Glu391fs)	Pathogenic
1703698	NM_001130682.3(GUCY1A1):c.1422del (p.Lys475fs)	Pathogenic
2423426	NC_000004.11:g.(?156618020)(156651383_?)del	Pathogenic
4686576	GUCY1A1, ARG593HIS (rs370478508)	Pathogenic
4720358	NM_001130682.3(GUCY1A1):c.1501C>T (p.Gln501Ter)	Pathogenic
4772288	NM_001130682.3(GUCY1A1):c.1119del (p.Ile373fs)	Pathogenic
4779848	NM_001130682.3(GUCY1A1):c.361C>T (p.Gln121Ter)	Pathogenic
559596	NM_001130682.3(GUCY1A1):c.1258C>T (p.Arg420Ter)	Pathogenic
559597	NM_001130682.3(GUCY1A1):c.1550G>A (p.Cys517Tyr)	Pathogenic
559599	NM_001130682.3(GUCY1A1):c.1954G>T (p.Gly652Ter)	Pathogenic
65427	NM_001130682.3(GUCY1A1):c.488dup (p.Leu163fs)	Pathogenic
3377733	NM_001130682.3(GUCY1A1):c.1886_1905del (p.Cys629fs)	Likely pathogenic
372598	NM_001130682.3(GUCY1A1):c.1909C>T (p.Arg637Ter)	Likely pathogenic

SpliceAI

2148 predictions. Top by Δscore:

Variant	Effect	Δscore
4:155667344:A:AG	acceptor_gain	1.0000
4:155667344:AGTGC:A	acceptor_gain	1.0000
4:155667345:G:GA	acceptor_gain	1.0000
4:155667345:GT:G	acceptor_gain	1.0000
4:155667345:GTGC:G	acceptor_gain	1.0000
4:155667345:GTGCG:G	acceptor_gain	1.0000
4:155667420:G:GG	donor_gain	1.0000
4:155703930:A:AG	acceptor_gain	1.0000
4:155703931:G:GA	acceptor_gain	1.0000
4:155703931:GTTT:G	acceptor_gain	1.0000
4:155713579:ACAAG:A	donor_loss	1.0000
4:155713580:CAAGG:C	donor_loss	1.0000
4:155713581:AAG:A	donor_loss	1.0000
4:155713582:AG:A	donor_loss	1.0000
4:155713583:GGTAG:G	donor_loss	1.0000
4:155713585:T:A	donor_loss	1.0000
4:155714653:G:GT	donor_gain	1.0000
4:155722032:TTTCA:T	acceptor_loss	1.0000
4:155722033:TTCA:T	acceptor_loss	1.0000
4:155722034:TCAGA:T	acceptor_loss	1.0000
4:155722035:CAG:C	acceptor_loss	1.0000
4:155722036:A:AG	acceptor_gain	1.0000
4:155722036:A:AT	acceptor_loss	1.0000
4:155722037:G:A	acceptor_loss	1.0000
4:155722037:G:GA	acceptor_gain	1.0000
4:155722037:GA:G	acceptor_gain	1.0000
4:155722037:GATGC:G	acceptor_gain	1.0000
4:155722188:TACAG:T	donor_loss	1.0000
4:155722190:CAG:C	donor_loss	1.0000
4:155722194:T:G	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000047810 (4:155729892 T>A), RS1000052426 (4:155727140 G>A), RS1000078748 (4:155729556 T>A), RS1000089396 (4:155686770 A>C), RS1000122861 (4:155704165 C>G), RS1000128198 (4:155685567 C>T), RS1000289554 (4:155710288 A>G), RS10003097 (4:155675618 C>A,G,T), RS1000328564 (4:155690972 A>G), RS1000332859 (4:155709842 A>G), RS10003392 (4:155733774 A>C,G), RS1000356912 (4:155697898 C>G), RS1000429068 (4:155716640 C>T), RS1000456346 (4:155705420 A>G), RS1000490242 (4:155673196 A>G)

Disease associations

OMIM: gene MIM:139396 | disease phenotypes: MIM:615750, MIM:252350

GenCC curated gene-disease

Disease	Classification	Inheritance
Moyamoya disease with early-onset achalasia	Strong	Autosomal recessive

Mondo (2): Moyamoya disease with early-onset achalasia (MONDO:0014331), moyamoya disease 1 (MONDO:0009649)

Orphanet (2): Moyamoya disease with early-onset achalasia (Orphanet:401945), Moyamoya disease (Orphanet:2573)

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000802	Impotence
HP:0000822	Hypertension
HP:0000965	Cutis marmorata
HP:0001269	Hemiparesis
HP:0001297	Stroke
HP:0001873	Thrombocytopenia
HP:0002015	Dysphagia
HP:0002140	Ischemic stroke
HP:0002197	Generalized-onset seizure
HP:0002571	Achalasia
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0011463	Childhood onset
HP:0011834	Moyamoya phenomenon
HP:0030402	Abnormal platelet aggregation
HP:0030880	Raynaud phenomenon
HP:0033505	Livedo reticularis
HP:0100659	Abnormal cerebral vascular morphology

GWAS associations

46 associations (top):

Study	Trait	p-value
GCST001227_20	Systolic blood pressure	1.000000e-06
GCST001228_9	Diastolic blood pressure	2.000000e-10
GCST001236_17	Blood pressure	3.000000e-07
GCST001587_5	Coronary heart disease	1.000000e-11
GCST002627_8	Hypertension	1.000000e-06
GCST002630_9	Systolic blood pressure	5.000000e-08
GCST002631_13	Diastolic blood pressure	6.000000e-07
GCST003098_19	Diabetic kidney disease	5.000000e-07
GCST003116_38	Coronary artery disease	6.000000e-09
GCST003117_33	Myocardial infarction	2.000000e-08
GCST003126_3	Influenza A (H1N1) severity	6.000000e-06
GCST004278_64	Pulse pressure	7.000000e-14
GCST004776_19	Systolic blood pressure	5.000000e-06
GCST004777_5	Diastolic blood pressure	2.000000e-06
GCST004787_4	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	1.000000e-09
GCST005194_49	Coronary artery disease	5.000000e-19
GCST005195_74	Coronary artery disease	3.000000e-23
GCST005196_77	Coronary artery disease	4.000000e-22
GCST006166_56	Diastolic blood pressure x alcohol consumption interaction (2df test)	2.000000e-18
GCST006166_7	Diastolic blood pressure x alcohol consumption interaction (2df test)	2.000000e-22
GCST006167_54	Mean arterial pressure x alcohol consumption interaction (2df test)	7.000000e-12
GCST006169_12	Diastolic blood pressure x alcohol consumption (light vs heavy) interaction (2df test)	3.000000e-09
GCST006169_26	Diastolic blood pressure x alcohol consumption (light vs heavy) interaction (2df test)	2.000000e-08
GCST006172_34	Mean arterial pressure x alcohol consumption (light vs heavy) interaction (2df test)	2.000000e-09
GCST006172_9	Mean arterial pressure x alcohol consumption (light vs heavy) interaction (2df test)	1.000000e-08
GCST006259_49	Systolic blood pressure	7.000000e-09
GCST006434_16	Systolic blood pressure x alcohol consumption interaction (2df test)	1.000000e-15
GCST006434_23	Systolic blood pressure x alcohol consumption interaction (2df test)	6.000000e-19
GCST006434_81	Systolic blood pressure x alcohol consumption interaction (2df test)	9.000000e-15
GCST007094_86	Diastolic blood pressure	3.000000e-19

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0006340	mean arterial pressure
EFO:0007743	influenza A severity measurement
EFO:0005763	pulse pressure measurement
EFO:0004329	alcohol drinking
EFO:0009928	Diuretic use measurement
EFO:0009930	Calcium channel blocker use measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0006917	spontaneous preterm birth
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004918	age at diagnosis
EFO:0004980	appendicular lean mass
EFO:0004587	lymphocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536991	Moyamoya disease 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2111348 (PROTEIN COMPLEX GROUP), CHEMBL3137281 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 8,203 (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
CHEMBL12610	BENZYDAMINE	4	8,193
CHEMBL5944803	FRESPACIGUAT	2	10

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Nitric oxide (NO)-sensitive (soluble) guanylyl cyclase

Binding affinities (BindingDB)

904 measured of 1287 human assays (1287 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(S)-3-(2-{4-amino-2-[6- fluoro-1-(2-fluorobenzyl)- 1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5- yl}-1,3-thiazol-4-yl)-2,2- dimethylpropanoic acid	KI	0.022 nM	US-10030027: Soluble guanylate cyclase stimulators
(S)-2-(3-(4-{4-amino-2- [1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3- yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5- yl}phenyl)propanamido)- 2-methylpropanoic acid	KI	0.026 nM	US-10030027: Soluble guanylate cyclase stimulators
3-(2-{4-amino-2- [6-chloro-1-(2- fluoro-3-methyl- benzyl)-1H- indazol-3-yl]-5- methyl-6-oxo- 6,7-dihydro-5H- pyrrolo[2,3-d] pyrimidin-5-yl}- 1,3-oxazol-4-yl)- 2,2-dimethyl- propanoic acid	KI	0.029 nM	US-10030027: Soluble guanylate cyclase stimulators
3-(2-{4-amino- 2-[1-(cyclohexyl- methyl)-1H- pyrazolo[3,4-b] pyridin-3-yl]-5- methyl-6-oxo- 6,7-dihydro-5H- pyrrolo[2,3-d] pyrimidin-5-yl}- 1,3-oxazol-4-yl)- 2,2-dimethyl- propanoic acid	KI	0.031 nM	US-10030027: Soluble guanylate cyclase stimulators
3-(2-{4-amino-2- [6-chloro-1-(2,3- difluorobenzyl)-1H- indazol-3-yl]-5- methyl-6-oxo- 6,7-dihydro-5H- pyrrolo[2,3-d] pyrimidin-5-yl}- 1,3-oxazol-4-yl)- 2,2-dimethyl- propanoic acid	KI	0.031 nM	US-10030027: Soluble guanylate cyclase stimulators
(S)-3-(2-{4-amino- 2-[6-chloro-1- (2,3,6-trifluoro- benzyl)-1H-indazol- 3-yl]-5-methyl- 6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d] pyrimidin-5-yl}- 1,3-thiazol-4-yl)- 2,2-dimethyl- propanoic acid	KI	0.031 nM	US-10030027: Soluble guanylate cyclase stimulators
(S)-(3-(4-{4-Amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoyl)glycine	KI	0.039 nM	US-10030027: Soluble guanylate cyclase stimulators
(S)-3-(2-{4-amino- 2-[6-fluoro-1-(3- fluorobenzyl)-1H- indazol-3-yl]-5- methyl-6-oxo- 6,7-dihydro-5H- pyrrolo[2,3-d] pyrimidin-5-yl}- 1,3-thiazol-4-yl)- 2,2-dimethyl- propanoic acid	KI	0.041 nM	US-10030027: Soluble guanylate cyclase stimulators
(5S,2S)-2-(3-(4-{4- amino-2-[1-(2- fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3- yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5- yl}phenyl)propanamido) butanoic acid	KI	0.042 nM	US-10030027: Soluble guanylate cyclase stimulators
(5S)-(3-(4-{4-amino-2-[1- (2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3- yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5- yl}phenyl)propanoyl)-L- alanine	KI	0.045 nM	US-10030027: Soluble guanylate cyclase stimulators
3-(2-{4-Amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic acid	KI	0.047 nM	US-10030027: Soluble guanylate cyclase stimulators
4-Amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-methyl-2-(2H-tetrazol-5-yl)propyl]oxazol-2-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one	KI	0.048 nM	US-10030027: Soluble guanylate cyclase stimulators
3-(2-{4-amino-2- [6-chloro-1-(2,3,6- trifluorobenzyl)-1H- indazol-3-yl]-5- methyl-6-oxo- 6,7-dihydro-5H- pyrrolo[2,3-d] pyrimidin-5-yl}- 1,3-oxazol-4-yl)- 2,2-dimethyl- propanoic acid	KI	0.049 nM	US-10030027: Soluble guanylate cyclase stimulators
3-(2-{4-amino-2- [1-(3-fluoro- benzyl)-1H- indazol-3-yl]-5- methyl-6-oxo- 6,7-dihydro-5H- pyrrolo[2,3-d] pyrimidin-5-yl}- 1,3-oxazol-4-yl)- 2,2-dimethyl- propanoic acid	KI	0.05 nM	US-10030027: Soluble guanylate cyclase stimulators
4-(2-{4-amino-2- [6-fluoro-1-(2- fluorobenzyl)-1H- indazol-3-yl]-5- methyl-6-oxo- 6,7-dihydro-5H- pyrrolo[2,3-d] pyrimidin-5-yl}- 1,3-oxazol-4-yl)- 2,2-dimethyl- butanoic acid	KI	0.052 nM	US-10030027: Soluble guanylate cyclase stimulators
3-(2-{4-amino-2- [1-(2,3-difluoro- benzyl)-6-fluoro- 1H-indazol-3-yl]- 5-methyl-6-oxo- 6,7-dihydro-5H- pyrrolo[2,3-d] pyrimidin-5-yl}- 1,3-oxazol-4-yl)- 2,2-dimethyl- propanoic acid	KI	0.052 nM	US-10030027: Soluble guanylate cyclase stimulators
(S)—N-((2H-Tetrazol-5-yl)methyl)-3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanamide	KI	0.056 nM	US-10030027: Soluble guanylate cyclase stimulators
4-(2-{4-amino-2-[6- chloro-1-(2-fluorobenzyl)- 1H-indazol-3-yl]-5- methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}-1,3- oxazol-4-yl)-2,2- difluorobutanoic acid	KI	0.057 nM	US-10030027: Soluble guanylate cyclase stimulators
(2E)-3-(4-{4- amino-2-[6- chloro-1-(2- fluorobenzyl)-1H- indazol-3-yl]-5- methyl-6-oxo- 6,7-dihydro-5H- pyrrolo[2,3-d] pyrimidin-5-yl} phenyl)prop-2- enoic acid	KI	0.057 nM	US-10030027: Soluble guanylate cyclase stimulators
(5S)-(3-(4-{4-amino-2-[1- (2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3- yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5- yl}phenyl)propanoyl)-D- serine	KI	0.058 nM	US-10030027: Soluble guanylate cyclase stimulators
3-(2-{4-amino-2-[6- chloro-1-(2-fluorobenzyl)- 1H-indazol-3-yl]-5- cyclopropyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}-1,3- oxazol-4-yl)-2,2- dimethylpropanoic acid	KI	0.058 nM	US-10030027: Soluble guanylate cyclase stimulators
(4-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenoxy)acetic acid	KI	0.058 nM	US-10030027: Soluble guanylate cyclase stimulators
(S)-3-(2-{4-amino-2-[6- chloro-1-(2- fluorobenzyl)-1H- indazol-3-yl]-5-methyl- 6-oxo-6,7-dihydro-5H- pyrrolo[2,3- d]pyrimidin-5-yl}-1,3- thiazol-4-yl)-2,2- dimethylpropanoic acid	KI	0.06 nM	US-10030027: Soluble guanylate cyclase stimulators
4-(2-{4-amino-2- [1-(2-fluorobenzyl)- 1H-pyrazolo[3,4-b] pyridin-3-yl]-5- methyl-6-oxo-6,7- dihydro-5H-pyrrolo [2,3-d]pyrimidin- 5-yl}-1,3-oxazol-4- yl)benzoic acid	KI	0.062 nM	US-10030027: Soluble guanylate cyclase stimulators
(S)-3-(4-{4-amino- 2-[6-chloro-1- (cyclopentylmethyl)- 1H-indazol-3-yl]- 5-methyl-6-oxo- 6,7-dihydro-5H- pyrrolo[2,3-d] pyrimidin-5-yl} phenyl)propanoic acid	KI	0.062 nM	US-10030027: Soluble guanylate cyclase stimulators
5-[4-(2H-tetrazol- 5-yl)pyridin-2- yl]-4-amino-2- [6-chloro-1-(2- fluorobenzyl)-1H- indazol-3-yl]-5- methyl-5,7- dihydro-6H- pyrrolo[2,3-d] pyrimidin-6-one	KI	0.062 nM	US-10030027: Soluble guanylate cyclase stimulators
(S)-3-(2-{4-amino-2-[1- (2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin- 3-yl]-5-methyl-6-oxo- 6,7-dihydro-5H- pyrrolo[2,3- d]pyrimidin-5-yl}-1,3- thiazol-4-yl)-2,2- dimethylpropanoic acid	KI	0.063 nM	US-10030027: Soluble guanylate cyclase stimulators
5-{4-[(2H-tetrazol- 5-yl)methyl] phenyl}-4-amino- 2-[6-chloro-2-(2- fluorobenzyl)-1H- indazol-3-yl]-5- methyl-5,7- dihydro-6H- pyrrolo[2,3-d] pyrimidin-6-one	KI	0.063 nM	US-10030027: Soluble guanylate cyclase stimulators
(S)-3-(4-{4-amino-2-[1-(2- fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl]- 5-methyl-6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin- 5-yl}phenyl)propanoic acid	KI	0.064 nM	US-10030027: Soluble guanylate cyclase stimulators
3-(3-{4-amino-2-[6-fluoro-1- (2-fluorobenzyl)-1H-indazol- 3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5- yl}phenyl)propanoic acid	KI	0.066 nM	US-10030027: Soluble guanylate cyclase stimulators
(S)-4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-(2H-tetrazol-5-yl)ethyl]phenyl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one	KI	0.066 nM	US-10030027: Soluble guanylate cyclase stimulators
3-(2-{4-amino- 2-[6-chloro-1- (2-fluorobenzyl)- 1H-indazol-3- yl]-5-methyl-6- oxo-6,7- dihydro-5H- pyrrolo[2,3-d] pyrimidin-5-yl) oxazol-4-yl}-2,2- dimethyl- propanoic acid	KI	0.067 nM	US-10030027: Soluble guanylate cyclase stimulators
(2E)-3-(4-{4- amino-2-[1-(2- fluorobenzyl)-1H- pyrazolo[3,4-b] pyridin-3-yl]-5- methyl-6-oxo- 6,7-dihydro-5H- pyrrolo[2,3-d] pyrimidin-5-yl} phenyl)prop-2- enoic acid	KI	0.067 nM	US-10030027: Soluble guanylate cyclase stimulators
(S)-3-(2-{4-amino- 5-methyl-6- oxo-2-[1-(2,3,6- trifluorobenzyl)- 1H-indazol-3-yl]- 6,7-dihydro-5H- pyrrolo[2,3-d] pyrimidin-5-yl}- 1,3-thiazol-4-yl)- 2,2-dimethyl- propanoic acid	KI	0.067 nM	US-10030027: Soluble guanylate cyclase stimulators
4-amino-2-[6- chloro-1-(2- fluorobenzyl)-1H- indazol-3-yl]-5- methyl-5-{4-[2- methyl-2-(2H- tetrazol-5-yl) propyl]-1,3- oxazol-2-yl}- 5,7-dihydro-6H- pyrrolo[2,3-d] pyrimidin-6-one	KI	0.068 nM	US-10030027: Soluble guanylate cyclase stimulators
4-Amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-[3-(1H-tetrazol-5-yl)phenyl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one	KI	0.068 nM	US-10030027: Soluble guanylate cyclase stimulators
4-amino-2-[6-chloro-1-[(2-fluorophenyl)methyl]indazol-3-yl]-5-methyl-5-[3-(2H-tetrazol-5-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-one	KI	0.068 nM	US-10428076: Soluble guanylate cyclase stimulators
4-(2-{4-amino-2- [6-chloro-1-(2- fluorobenzyl)-1H- indazol-3-yl]-5- methyl-6-oxo- 6,7-dihydro-5H- pyrrolo[2,3-d] pyrimidin-5-yl}- 1,3-oxazol-4-yl)- 2,2-dimethyl- butanoic acid	KI	0.07 nM	US-10030027: Soluble guanylate cyclase stimulators
(S)-3-(2-{4-amino- 2-[1-(2,3- difluorobenzyl)-6- fluoro-1H-indazol- 3-yl]-5-methyl-6- oxo-6,7-dihydro- 5H-pyrrolo[2,3-d] pyrimidin-5-yl}- 1,3-thiazol-4-yl)- 2,2-dimethyl- propanoic acid	KI	0.07 nM	US-10030027: Soluble guanylate cyclase stimulators
3-(2-{4-amino-2- [6-fluoro-1-(2- fluoro-3-methyl- benzyl)-1H- indazol-3-yl]-5- methyl-6-oxo- 6,7-dihydro-5H- pyrrolo[2,3-d] pyrimidin-5-yl}- 1,3-oxazol-4-yl)- 2,2-dimethyl- propanoic acid	KI	0.072 nM	US-10030027: Soluble guanylate cyclase stimulators
6-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}picolinic acid	KI	0.073 nM	US-10030027: Soluble guanylate cyclase stimulators
3-{2-[4-amino-2-{6- chloro-1-[4- methylcyclohexylmethyl]- 1H-indazol-3-yl}-5- methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl]-1,3- oxazol-4-yl}-2,2- dimethylpropanoic acid	KI	0.074 nM	US-10030027: Soluble guanylate cyclase stimulators
(S)-4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl]phenyl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one	KI	0.074 nM	US-10030027: Soluble guanylate cyclase stimulators
3-[1-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyrrolidin-3-yl]propanoic acid	KI	0.074 nM	US-10030027: Soluble guanylate cyclase stimulators
3-[2-[4-[(5S)-2-[6-chloro-1-[(2-fluorophenyl)methyl]indazol-3-yl]-5-methyl-6-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl]ethyl]-1,2,4-oxadiazolidin-5-one	KI	0.074 nM	US-10428076: Soluble guanylate cyclase stimulators
(S)-3-(4-{4-amino-2-[6- chloro-1-(2,6- difluorobenzyl)-1H-indazol- 3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5- yl}phenyl)propanoic acid	KI	0.075 nM	US-10030027: Soluble guanylate cyclase stimulators
4-(2-{4-amino-2- [1-(2-fluorobenzyl)- 1H-pyrazolo[3,4-b] pyridin-3-yl]-5- methyl-6-oxo-6,7- dihydro-5H-pyrrolo [2,3-d]pyrimidin- 5-yl}-1,3-thiazol-4- yl)benzoic acid	KI	0.075 nM	US-10030027: Soluble guanylate cyclase stimulators
(S)-4-amino-2- [1-(2-fluoro- benzyl)-1H- pyrazolo[3,4-b] pyridin-3-yl]- 5-methyl-5-{4- [2-(2H-tetrazol- 5-yl)ethyl] phenyl}-5,7- dihydro-6H- pyrrolo[2,3-d] pyrimidin-6-one	KI	0.075 nM	US-10030027: Soluble guanylate cyclase stimulators
(S)-3-(2-{4-amino- 2-[6-chloro-1-(2,6- difluorobenzyl)-1H- indazol-3-yl]-5- methyl-6-oxo- 6,7-dihydro-5H- pyrrolo[2,3-d] pyrimidin-5-yl}- 1,3-thiazol-4-yl)- 2,2-dimethyl- propanoic acid	KI	0.076 nM	US-10030027: Soluble guanylate cyclase stimulators
3-{2-[4-amino-5-methyl- 2-{1-[4- methylcyclohexylmethyl]- 1H-pyrazolo[3,4- b]pyridin-3-yl}-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl]-1,3- oxazol-4-yl}-2,2- dimethylpropanoic acid	KI	0.077 nM	US-10030027: Soluble guanylate cyclase stimulators

ChEMBL bioactivities

909 potent at pChembl≥5 of 962 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.66	Ki	0.022	nM	CHEMBL5814188
10.59	Ki	0.026	nM	CHEMBL5961042
10.54	Ki	0.029	nM	CHEMBL5937094
10.51	Ki	0.031	nM	CHEMBL5962881
10.51	Ki	0.031	nM	CHEMBL5896066
10.51	Ki	0.031	nM	CHEMBL5828124
10.41	Ki	0.039	nM	CHEMBL5754765
10.39	Ki	0.041	nM	CHEMBL6025572
10.38	Ki	0.042	nM	CHEMBL5943807
10.35	Ki	0.045	nM	CHEMBL5924970
10.33	Ki	0.047	nM	CHEMBL5980517
10.32	Ki	0.048	nM	CHEMBL5989618
10.31	Ki	0.049	nM	CHEMBL6038148
10.30	Ki	0.05	nM	CHEMBL5915567
10.28	Ki	0.052	nM	CHEMBL6021981
10.28	Ki	0.052	nM	CHEMBL6053909
10.25	Ki	0.056	nM	CHEMBL5838947
10.24	Ki	0.058	nM	CHEMBL5925728
10.24	Ki	0.057	nM	CHEMBL6031103
10.24	Ki	0.058	nM	CHEMBL6006393
10.24	Ki	0.057	nM	CHEMBL5959396
10.24	Ki	0.058	nM	CHEMBL5981554
10.22	Ki	0.06	nM	CHEMBL5872155
10.21	Ki	0.062	nM	CHEMBL6055856
10.21	Ki	0.062	nM	CHEMBL6011397
10.21	Ki	0.062	nM	CHEMBL5946879
10.20	Ki	0.063	nM	CHEMBL5973404
10.20	Ki	0.063	nM	CHEMBL6050464
10.19	Ki	0.064	nM	CHEMBL5941930
10.18	Ki	0.066	nM	CHEMBL5850021
10.18	Ki	0.066	nM	CHEMBL5754222
10.17	Ki	0.067	nM	CHEMBL5758630
10.17	Ki	0.067	nM	CHEMBL5842014
10.17	Ki	0.067	nM	CHEMBL6019970
10.17	Ki	0.068	nM	CHEMBL5996734
10.17	Ki	0.068	nM	CHEMBL5870392
10.15	Ki	0.07	nM	CHEMBL5979143
10.15	Ki	0.07	nM	CHEMBL5977775
10.14	Ki	0.072	nM	CHEMBL6065117
10.14	Ki	0.073	nM	CHEMBL6023523
10.13	Ki	0.074	nM	CHEMBL6064339
10.13	Ki	0.074	nM	CHEMBL5908747
10.13	Ki	0.074	nM	CHEMBL5862357
10.12	Ki	0.075	nM	CHEMBL5855606
10.12	Ki	0.075	nM	CHEMBL5981113
10.12	Ki	0.075	nM	CHEMBL5793164
10.12	Ki	0.076	nM	CHEMBL5965599
10.11	Ki	0.078	nM	CHEMBL5828379
10.11	Ki	0.077	nM	CHEMBL6032838
10.10	Ki	0.079	nM	CHEMBL5972747

PubChem BioAssay actives

72 with measured affinity, of 284 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
1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]piperidine-4-carboxylic acid	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0070	uM
1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]piperidin-4-ol	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0100	uM
5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-N-methylpyrimidin-4-amine	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0200	uM
3-[1-[(2-fluorophenyl)methyl]-3-(5-fluoro-4-piperidin-1-ylpyrimidin-2-yl)pyrazol-5-yl]-1,2-oxazole	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0270	uM
1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]piperidin-3-ol	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0330	uM
(2R,3S)-1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]-3-methylpiperidine-2-carboxylic acid	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0330	uM
[1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]piperidin-2-yl]methanol	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0350	uM
(2S,3R)-1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]-3-methylpiperidine-2-carboxylic acid	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0400	uM
5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-N-(2-morpholin-4-ylethyl)pyrimidin-4-amine	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0410	uM
4-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]morpholine	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0500	uM
1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]piperidine-3-carboxylic acid	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0550	uM
3-[1-[(2-fluorophenyl)methyl]-3-(5-fluoro-4-pyrrolidin-1-ylpyrimidin-2-yl)pyrazol-5-yl]-1,2-oxazole	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0830	uM
5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-1H-pyrimidin-6-one	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.0970	uM
methyl N-[4,6-diamino-2-[3-[(2,3,5-trifluorophenyl)methyl]indazol-1-yl]pyrimidin-5-yl]-N-methylcarbamate	1677320: Activation of human sGC subunit alpha1/beta1 expressed in CHO cells assessed as cGMP production by CASA assay	ec50	0.1100	uM
6-amino-2-[3-[(2-fluorophenyl)methyl]indazol-1-yl]-7-methyl-9H-purin-8-one	1677320: Activation of human sGC subunit alpha1/beta1 expressed in CHO cells assessed as cGMP production by CASA assay	ec50	0.1200	uM
3-[1-[(2-fluorophenyl)methyl]-3-(5-fluoro-4-piperazin-1-ylpyrimidin-2-yl)pyrazol-5-yl]-1,2-oxazole	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.1200	uM
(2R)-1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]piperidine-2-carboxylic acid	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.1200	uM
5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-amine	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.1300	uM
6-amino-2-[5-chloro-3-[(2-fluorophenyl)methyl]indazol-1-yl]-7-methyl-9H-purin-8-one	1677320: Activation of human sGC subunit alpha1/beta1 expressed in CHO cells assessed as cGMP production by CASA assay	ec50	0.1400	uM
3-[3-[4-(3,3-difluoropiperidin-1-yl)-5-fluoropyrimidin-2-yl]-1-[(2-fluorophenyl)methyl]pyrazol-5-yl]-1,2-oxazole	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.1500	uM
4-amino-2-[3-[(2-fluorophenyl)methyl]indazol-1-yl]-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one	1677320: Activation of human sGC subunit alpha1/beta1 expressed in CHO cells assessed as cGMP production by CASA assay	ec50	0.1600	uM
5-(4-chlorophenyl)sulfonyl-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.1600	uM
5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-thiazol-3-yl)pyrazol-3-yl]-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.1800	uM
6-amino-7-ethyl-2-[3-[(2-fluorophenyl)methyl]indazol-1-yl]-9H-purin-8-one	1677320: Activation of human sGC subunit alpha1/beta1 expressed in CHO cells assessed as cGMP production by CASA assay	ec50	0.2000	uM
(2S)-1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]piperidine-2-carboxylic acid	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.2000	uM
2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-amine	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.2400	uM
5-fluoro-2-[1-[(2-fluoro-3-methylphenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.2400	uM
4-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]-1,4-thiazinane 1,1-dioxide	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.2400	uM
3-[3-[4-(4,4-difluoropiperidin-1-yl)-5-fluoropyrimidin-2-yl]-1-[(2-fluorophenyl)methyl]pyrazol-5-yl]-1,2-oxazole	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.2500	uM
methyl N-[4,6-diamino-2-[3-[(2,5-difluorophenyl)methyl]indazol-1-yl]pyrimidin-5-yl]-N-methylcarbamate	1677320: Activation of human sGC subunit alpha1/beta1 expressed in CHO cells assessed as cGMP production by CASA assay	ec50	0.2700	uM
methyl N-[4,6-diamino-2-[3-[(2,3,6-trifluorophenyl)methyl]indazol-1-yl]pyrimidin-5-yl]-N-methylcarbamate	1677320: Activation of human sGC subunit alpha1/beta1 expressed in CHO cells assessed as cGMP production by CASA assay	ec50	0.2700	uM
5-fluoro-2-[1-[(3-fluorothiophen-2-yl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.2800	uM
methyl N-[4,6-diamino-2-[3-[(2,3-difluorophenyl)methyl]indazol-1-yl]pyrimidin-5-yl]-N-methylcarbamate	1677320: Activation of human sGC subunit alpha1/beta1 expressed in CHO cells assessed as cGMP production by CASA assay	ec50	0.3000	uM
6-amino-2-[3-[(2-fluorophenyl)methyl]indazol-1-yl]-7,9-dihydropurin-8-one	1677320: Activation of human sGC subunit alpha1/beta1 expressed in CHO cells assessed as cGMP production by CASA assay	ec50	0.3000	uM
methyl N-[4,6-diamino-2-[3-[(2-fluorophenyl)methyl]indazol-1-yl]pyrimidin-5-yl]-N-methylcarbamate	1677320: Activation of human sGC subunit alpha1/beta1 expressed in CHO cells assessed as cGMP production by CASA assay	ec50	0.3100	uM
3-[3-(5-fluoro-4-methoxypyrimidin-2-yl)-1-[(2-fluorophenyl)methyl]pyrazol-5-yl]-1,2-oxazole	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.3200	uM
methyl N-[4,6-diamino-2-[5-chloro-3-[(2-fluorophenyl)methyl]indazol-1-yl]pyrimidin-5-yl]-N-methylcarbamate	1677320: Activation of human sGC subunit alpha1/beta1 expressed in CHO cells assessed as cGMP production by CASA assay	ec50	0.3500	uM
5-(benzenesulfonyl)-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.3500	uM
2-[1-[(2,3-difluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-5-fluoro-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.3700	uM
2-[1-[(3-chloro-2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-5-fluoro-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.3800	uM
2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-6-oxo-1H-pyrimidine-5-carbonitrile	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.5000	uM
2-[1-[(2,4-difluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-5-fluoro-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.5300	uM
5-chloro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.5900	uM
methyl N-[4,6-diamino-2-[5-chloro-3-[(2,3,6-trifluorophenyl)methyl]indazol-1-yl]pyrimidin-5-yl]carbamate	1677320: Activation of human sGC subunit alpha1/beta1 expressed in CHO cells assessed as cGMP production by CASA assay	ec50	0.6700	uM
methyl N-[4,6-diamino-2-[5-chloro-3-[(2,3,6-trifluorophenyl)methyl]indazol-1-yl]pyrimidin-5-yl]-N-methylcarbamate	1677320: Activation of human sGC subunit alpha1/beta1 expressed in CHO cells assessed as cGMP production by CASA assay	ec50	0.7000	uM
2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-N-methyl-6-oxo-N-phenyl-1H-pyrimidine-5-sulfonamide	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.7300	uM
2-[1-benzyl-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-5-fluoro-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.8800	uM
2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]-5-methylsulfonyl-1H-pyrimidin-6-one	1304082: Activation of SGC in HEK293 cells assessed as cGMP production after 20 mins by LC-MS/MS analysis in presence of NO-donor DETA-NONOate	ec50	0.9000	uM
methyl N-[4,6-diamino-2-[5-fluoro-3-[(2-fluorophenyl)methyl]indazol-1-yl]pyrimidin-5-yl]-N-methylcarbamate	1677320: Activation of human sGC subunit alpha1/beta1 expressed in CHO cells assessed as cGMP production by CASA assay	ec50	0.9600	uM
(2S)-1-[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]pyrrolidine-2-carboxylic acid	1757088: Activation of sGC (unknown origin) in presence of DETA-NO by Glosensor cGMP assay	ec50	0.9700	uM

CTD chemical–gene interactions

67 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	4
methylselenic acid	decreases expression, decreases reaction, affects expression	3
Cyclic GMP	increases abundance, affects binding, increases chemical synthesis, decreases reaction	3
3-(5’-hydroxymethyl-2’-furyl)-1-benzylindazole	affects binding, affects folding, decreases reaction, increases abundance	2
1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one	affects binding, affects folding, decreases reaction, increases activity, increases reaction (+1 more)	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Benzo(a)pyrene	decreases methylation, increases methylation, increases mutagenesis	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Nitric Oxide	affects binding, affects folding, increases response to substance	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects cotreatment, affects expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
ascorbate-2-phosphate	affects binding, affects cotreatment, increases expression	1
sodium arsenite	increases expression	1
tetrabromobisphenol A	increases expression	1
perfluorooctanoic acid	affects cotreatment, affects expression	1
protoporphyrin IX	affects binding, increases activity, increases reaction	1
potassium ferricyanide	decreases reaction, increases activity, affects binding	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	affects expression, affects cotreatment	1
1,1-diethyl-2-hydroxy-2-nitrosohydrazine	affects binding, increases activity, decreases reaction	1
entinostat	affects cotreatment, decreases expression	1
3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine	affects binding, increases activity, increases reaction	1
KMUP 1	increases expression	1

ChEMBL screening assays

45 unique, capped per target: 40 binding, 5 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1918701	Binding	Activation of human soluble guanylate cyclase assessed as production of cGMP in presence of nitric oxide donor, SIN-1 by LC-MS enzyme assay	Acidic triazoles as soluble guanylate cyclase stimulators. — Bioorg Med Chem Lett
CHEMBL865676	Functional	Effect on cGMP production in porcine iris-ciliary body at 10 uM	Synthesis and ocular effects of imidazole nitrolic acid and amidoxime esters. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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