PDE2A

Summary

PDE2A (phosphodiesterase 2A, HGNC:8777) is a protein-coding gene on chromosome 11q13.4, encoding cGMP-dependent 3’,5’-cyclic phosphodiesterase (O00408). cGMP-activated cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.

Enables several functions, including 3’,5’-cyclic-nucleotide phosphodiesterase activity; anion binding activity; and metal ion binding activity. Involved in several processes, including cellular response to cytokine stimulus; regulation of signal transduction; and regulation of vascular permeability. Located in several cellular components, including cytosol; mitochondrial membrane; and perinuclear region of cytoplasm.

Source: NCBI Gene 5138 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual developmental disorder with paroxysmal dyskinesia or seizures (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 375 total — 5 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 25
• Druggable target: yes — 12 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002599

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8777
Approved symbol	PDE2A
Name	phosphodiesterase 2A
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000186642
Ensembl biotype	protein_coding
OMIM	602658
Entrez	5138

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 14 protein_coding, 8 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000334456, ENST00000376450, ENST00000418754, ENST00000420501, ENST00000441209, ENST00000444035, ENST00000475807, ENST00000485058, ENST00000490749, ENST00000535701, ENST00000536308, ENST00000536458, ENST00000536918, ENST00000537631, ENST00000538299, ENST00000538749, ENST00000539367, ENST00000540345, ENST00000540380, ENST00000541998, ENST00000542223, ENST00000542969, ENST00000543575, ENST00000543750, ENST00000544239, ENST00000544570, ENST00000546038

RefSeq mRNA: 4 — MANE Select: NM_002599 NM_001143839, NM_001146209, NM_001243784, NM_002599

CCDS: CCDS44670, CCDS53678, CCDS73345, CCDS8216

Canonical transcript exons

ENST00000334456 — 31 exons

Exon	Start	End
ENSE00001836179	72576141	72577594
ENSE00001920521	72674137	72674422
ENSE00003509911	72582444	72582566
ENSE00003527140	72589175	72589240
ENSE00003539877	72584872	72584944
ENSE00003542819	72590427	72590580
ENSE00003544701	72579534	72579608
ENSE00003552170	72578233	72578339
ENSE00003562606	72608662	72608751
ENSE00003563206	72581357	72581479
ENSE00003577129	72597510	72597619
ENSE00003591282	72578897	72579009
ENSE00003594101	72585554	72585593
ENSE00003600020	72578476	72578514
ENSE00003600335	72589751	72589792
ENSE00003607412	72580577	72580624
ENSE00003612344	72585371	72585434
ENSE00003617818	72590192	72590244
ENSE00003620083	72642254	72642326
ENSE00003635557	72581877	72581947
ENSE00003640580	72579284	72579383
ENSE00003641523	72584201	72584313
ENSE00003646487	72583438	72583515
ENSE00003657003	72589907	72589981
ENSE00003657645	72596593	72596648
ENSE00003679062	72586070	72586181
ENSE00003679787	72580886	72580973
ENSE00003683488	72591297	72591356
ENSE00003686558	72588784	72588914
ENSE00003784190	72605138	72605226
ENSE00003791334	72584551	72584728

Expression profiles

Bgee: expression breadth ubiquitous, 224 present calls, max score 98.38.

FANTOM5 (CAGE): breadth broad, TPM avg 5.2001 / max 187.2796, expressed in 509 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121176	2.6306	390
121178	1.7756	128
121177	0.3036	110
121180	0.1856	42
121179	0.1034	57
121166	0.0672	28
121172	0.0615	15
121173	0.0427	13
121171	0.0193	4
121174	0.0089	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
spleen	UBERON:0002106	98.38	gold quality
right frontal lobe	UBERON:0002810	97.34	gold quality
prefrontal cortex	UBERON:0000451	97.32	gold quality
omental fat pad	UBERON:0010414	97.28	gold quality
peritoneum	UBERON:0002358	97.20	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.83	gold quality
frontal cortex	UBERON:0001870	96.66	gold quality
cingulate cortex	UBERON:0003027	96.59	gold quality
anterior cingulate cortex	UBERON:0009835	96.59	gold quality
adipose tissue of abdominal region	UBERON:0007808	96.56	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.56	gold quality
orbitofrontal cortex	UBERON:0004167	96.19	gold quality
neocortex	UBERON:0001950	96.12	gold quality
CA1 field of hippocampus	UBERON:0003881	96.06	gold quality
nucleus accumbens	UBERON:0001882	96.04	gold quality
subcutaneous adipose tissue	UBERON:0002190	95.92	gold quality
cortical plate	UBERON:0005343	95.88	gold quality
putamen	UBERON:0001874	95.76	gold quality
caudate nucleus	UBERON:0001873	95.71	gold quality
amygdala	UBERON:0001876	95.70	gold quality
cerebral cortex	UBERON:0000956	95.65	gold quality
postcentral gyrus	UBERON:0002581	95.65	gold quality
superior frontal gyrus	UBERON:0002661	95.42	gold quality
telencephalon	UBERON:0001893	95.28	gold quality
parietal lobe	UBERON:0001872	95.19	gold quality
temporal lobe	UBERON:0001871	95.13	gold quality
entorhinal cortex	UBERON:0002728	95.12	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.90	gold quality
frontal pole	UBERON:0002795	94.68	gold quality
Ammon’s horn	UBERON:0001954	94.54	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.44
E-MTAB-9067	yes	7.13

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

67 targeting PDE2A, 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-6873-3P	100.00	71.42	2626
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AN	99.97	70.91	2817
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-377-5P	99.70	65.28	712
HSA-MIR-6086	99.70	65.38	699
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119

Literature-anchored findings (GeneRIF, showing 25)

• Inhibition of PDE2 resulted in higher levels of intracellular cAMP than inhibition of PDE3A suggesting this PDE may be the more important regulator of cAMP in human platelets. (PMID:12038792)
• TNF-alpha-mediated up-regulation of PDE2 may destabilize endothelial barrier function in sepsis (PMID:15650061)
• Phosphodiesterase 2 mediates redox-sensitive endothelial cell proliferation and angiogenesis by thrombin via Rac1 and NADPH oxidase 2. (PMID:19390057)
• report the X-ray crystal structures of a PDE protein that includes both catalytic and regulatory domains, namely, PDE2A containing the N-terminal GAF domains and the catalytic domain. (PMID:19828435)
• found in smooth muscle wall of blood vessels transversing the clitoral supepithelial and stromal space (PMID:21697861)
• the phosphodiesterase 2A isoform localized to mitochondria regulates respiration (PMID:21724846)
• Active site similarity between human and Plasmodium falciparum phosphodiesterases: considerations for antimalarial drug design (PMID:21766240)
• Our results demonstrated that the PDE2A2 variant carrying point mutations is expressed in PMP cells and may affect cell cycle progression by modulating cyclin A expression. (PMID:23381931)
• PDE2 overexpression in healthy cardiomyocytes reduces the rise in cyclic AMP levels and L-type calcium current amplitude, and abolishes the inotropic effect following acute beta-adrenergic receptor stimulation. (PMID:23810893)
• This study reports the X-ray crystal structure of PDE2A in complex with a highly selective, nanomolar inhibitor (BAY60-7550) at 1.9 A resolution, and the structure of apo PDE2 at 2.0 A resolution. (PMID:23899287)
• PDE2A is involved in growth and invasion of human malignant melanoma PMP cells. (PMID:24705027)
• curcumin exerts its in vitro anti-angiogenic and in vivo anti-tumour properties through combined PDE2 and PDE4 inhibition (PMID:25230992)
• Lu AF33241 represents a novel PDE2A/PDE10A inhibitor tool which can penetrate the blood brain barrier. (PMID:25941078)
• Epigenetic regulation of phosphodiesterases 2A and 3A underlies compromised beta-adrenergic Signaling in an induced pluripotent stem cell model of dilated cardiomyopathy. (PMID:26095046)
• the well-known interaction between AIP and 2 different isoforms of phosphodiesterases (PDEs), PDE2A3 and PDE4A5, is of particular interest. While the interaction with over-expressed AIP does not seem to affect PDE2A3 function, the reported effect on PDE4A5 is, in contrast, reduced enzymatic activity. (PMID:28427099)
• Phosphodiesterases PDE2A and PDE10A both change mRNA expression in the human brain with age, but only PDE2A changes in a region-specific manner with psychiatric disease. (PMID:32119913)
• A Homozygous Splicing Mutation in PDE2A in a Family With Atypical Rett Syndrome. (PMID:32196122)
• A Novel Inhibition Modality for Phosphodiesterase 2A. (PMID:32343157)
• Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia. (PMID:32467598)
• Phosphodiesterase 2A2 regulates mitochondria clearance through Parkin-dependent mitophagy. (PMID:33087821)
• Phosphodiesterase 2A and 3B variants are associated with primary aldosteronism. (PMID:33112806)
• miR-139/PDE2A-Notch1 feedback circuit represses stemness of gliomas by inhibiting Wnt/beta-catenin signaling. (PMID:34512162)
• Low Expression of Phosphodiesterase 2 (PDE2A) Promotes the Progression by Regulating Mitochondrial Morphology and ATP Content and Predicts Poor Prognosis in Hepatocellular Carcinoma. (PMID:36611861)
• Phosphodiesterase 2 and Its Isoform A as Therapeutic Targets in the Central Nervous System Disorders. (PMID:37855295)
• The phosphodiesterase 2A controls lymphatic junctional maturation via cGMP-dependent notch signaling. (PMID:38159569)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000079064
danio_rerio	pde2a	ENSDARG00000114444
mus_musculus	Pde2a	ENSMUSG00000110195
rattus_norvegicus	Pde2a	ENSRNOG00000019560
drosophila_melanogaster	Pde11	FBGN0085370
caenorhabditis_elegans		WBGENE00011146

Paralogs (20): PDE4A (ENSG00000065989), PDE8A (ENSG00000073417), PDE6C (ENSG00000095464), PDE4C (ENSG00000105650), PDE10A (ENSG00000112541), PDE8B (ENSG00000113231), PDE4D (ENSG00000113448), PDE1A (ENSG00000115252), PDE1B (ENSG00000123360), PDE11A (ENSG00000128655), PDE6A (ENSG00000132915), PDE6B (ENSG00000133256), PDE5A (ENSG00000138735), PDE3B (ENSG00000152270), PDE1C (ENSG00000154678), PDE9A (ENSG00000160191), PDE7B (ENSG00000171408), PDE3A (ENSG00000172572), PDE4B (ENSG00000184588), PDE7A (ENSG00000205268)

Protein

Protein identifiers

cGMP-dependent 3’,5’-cyclic phosphodiesterase — O00408 (reviewed: O00408)

Alternative names: Cyclic GMP-stimulated phosphodiesterase

All UniProt accessions (16): C9JPD5, E9PEF1, F5GXX2, F5H130, F5H143, F5H1D7, F5H2R8, F5H2V7, F5H2Z0, F5H3Z7, F5H5P8, O00408, H0YFL1, H0YG13, H0YGL2, H7C009

UniProt curated annotations — full annotation on UniProt →

Function. cGMP-activated cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Has a higher efficiency with cGMP compared to cAMP. Plays a role in cell growth and migration. Regulates mitochondrial cAMP levels and respiration. Involved in the regulation of mitochondria morphology/dynamics and apoptotic cell death via local modulation of cAMP/PKA signaling in the mitochondrion, including the monitoring of local cAMP levels at the outer mitochondrial membrane and of PKA-dependent phosphorylation of DNM1L.

Subunit / interactions. Homodimer.

Subcellular location. Cell membrane Mitochondrion matrix. Mitochondrion inner membrane. Mitochondrion outer membrane Cytoplasm Mitochondrion.

Tissue specificity. Widely expressed. Expressed in brain, with high expression observed in the corpus striatum. Also expressed in heart, placenta, lung, skeletal muscle, kidney and pancreas.

Disease relevance. Intellectual developmental disorder with paroxysmal dyskinesia or seizures (IDDPADS) [MIM:619150] An autosomal recessive disorder characterized by global developmental delay, impaired intellectual development, language delay, and early-onset paroxysmal hyperkinetic movement disorder that manifests as sudden falls or backward propulsion, eye or head deviation, and dystonic limb posturing followed by chorea and dyskinetic movements. Some patients may also develop epileptic seizures or only have seizures without a movement disorder. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The 3’,5’-cyclic-AMP phosphodiesterase activity is stimulated by 3’,5’-cyclic GMP.

Cofactor. Binds 2 divalent metal cations per subunit. Site 1 may preferentially bind zinc ions. Binds 2 divalent metal cations per subunit. Site 2 has a preference for magnesium ions.

Domain organisation. The GAF 1 domain functions as a dimerization domain. The GAF 2 domains binds cGMP, which acts as an allosteric activator.

Miscellaneous. Soluble form. Contains a transit peptide at positions 1-17.

Similarity. Belongs to the cyclic nucleotide phosphodiesterase family. PDE2 subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
O00408-1	PDE2A3	yes
O00408-2	PDE2A1
O00408-3	PDE2A2
O00408-4	PDE2A4
O00408-5	5
O00408-6	6

RefSeq proteins (4): NP_001137311, NP_001139681, NP_001230713, NP_002590* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002073	PDEase_catalytic_dom	Domain
IPR003018	GAF	Domain
IPR003607	HD/PDEase_dom	Domain
IPR023088	PDEase	Family
IPR023174	PDEase_CS	Conserved_site
IPR029016	GAF-like_dom_sf	Homologous_superfamily
IPR036971	PDEase_catalytic_dom_sf	Homologous_superfamily

Pfam: PF00233, PF01590

Enzyme classification (BRENDA):

• EC 3.1.4.17 — 3’,5’-cyclic-nucleotide phosphodiesterase (BRENDA: 27 organisms, 83 substrates, 296 inhibitors, 106 Km, 31 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
3’,5’-CAMP	0.0001–7	41
3’,5’-CGMP	—	23
CAMP	0.0002–1.6	15
CGMP	0.0002–1	12
2’,3’-CAMP	0.0038–0.0052	2
5’-AMP	0.0014–0.0016	2
5’-ATP	0.0033–0.0125	2
5’-PAPA	0.204	1
5’-PAPG	0.355	1
ADENOSINE 3’,5’-CYCLIC PHOSPHATE	0.012	1
GUANOSINE 3’,5’-CYCLIC PHOSPHATE	0.025	1

Catalyzed reactions (Rhea), 3 shown:

• a nucleoside 3’,5’-cyclic phosphate + H2O = a nucleoside 5’-phosphate + H(+) (RHEA:14653)
• 3’,5’-cyclic GMP + H2O = GMP + H(+) (RHEA:16957)
• 3’,5’-cyclic AMP + H2O = AMP + H(+) (RHEA:25277)

UniProt features (107 total): helix 34, strand 17, mutagenesis site 12, binding site 10, turn 9, splice variant 6, sequence variant 4, sequence conflict 4, lipid moiety-binding region 3, domain 3, region of interest 2, initiator methionine 1, chain 1, active site 1

Structure

Experimental structures (PDB)

44 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5U00	X-RAY DIFFRACTION	1.41
6C7E	X-RAY DIFFRACTION	1.43
6EZF	X-RAY DIFFRACTION	1.5
6CYC	X-RAY DIFFRACTION	1.54
3ITU	X-RAY DIFFRACTION	1.58
5TZW	X-RAY DIFFRACTION	1.59
5TZH	X-RAY DIFFRACTION	1.6
5TZZ	X-RAY DIFFRACTION	1.6
6CYB	X-RAY DIFFRACTION	1.62
6C7G	X-RAY DIFFRACTION	1.68
6CYD	X-RAY DIFFRACTION	1.69
1Z1L	X-RAY DIFFRACTION	1.7
5TZA	X-RAY DIFFRACTION	1.7
6C7I	X-RAY DIFFRACTION	1.71
4JIB	X-RAY DIFFRACTION	1.72
5TZ3	X-RAY DIFFRACTION	1.72
5U7D	X-RAY DIFFRACTION	1.75
6B97	X-RAY DIFFRACTION	1.76
6C7D	X-RAY DIFFRACTION	1.79
6C7F	X-RAY DIFFRACTION	1.82
6C7J	X-RAY DIFFRACTION	1.85
5VP1	X-RAY DIFFRACTION	1.86
6B96	X-RAY DIFFRACTION	1.88
6ZQZ	X-RAY DIFFRACTION	1.88
4D08	X-RAY DIFFRACTION	1.9
4HTX	X-RAY DIFFRACTION	1.9
5TZX	X-RAY DIFFRACTION	1.9
5U7J	X-RAY DIFFRACTION	1.9
6B98	X-RAY DIFFRACTION	1.97
4HTZ	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00408-F1	84.17	0.53

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 (1): 656 (proton donor)

Ligand- & substrate-binding residues (10): 465; 488; 499; 660; 696; 697; 697; 808; 431; 446

Post-translational modifications (3): 2, 5, 11

Mutagenesis-validated functional residues (12):

Position	Phenotype
811	decreased 3’,5’-cyclic-amp phosphodiesterase activity. no effect on 3’,5’-cyclic-gmp phosphodiesterase activity.
812	no effect on 3’,5’-cyclic-amp phosphodiesterase activity. decreased 3’,5’-cyclic-gmp phosphodiesterase activity.
812	loss of 3’,5’-cyclic-amp phosphodiesterase activity. loss of 3’,5’-cyclic-gmp phosphodiesterase activity.
819	loss of 3’,5’-cyclic-amp phosphodiesterase activity. loss of 3’,5’-cyclic-gmp phosphodiesterase activity.
826	decreased 3’,5’-cyclic-amp phosphodiesterase activity. increased 3’,5’-cyclic-gmp phosphodiesterase activity.
827	decreased 3’,5’-cyclic-amp phosphodiesterase activity. loss of 3’,5’-cyclic-gmp phosphodiesterase activity.
827	loss of 3’,5’-cyclic-amp phosphodiesterase activity. decreased 3’,5’-cyclic-gmp phosphodiesterase activity.
827	loss of 3’,5’-cyclic-amp phosphodiesterase activity. loss of 3’,5’-cyclic-gmp phosphodiesterase activity.
847	decreased 3’,5’-cyclic-amp phosphodiesterase activity. loss of 3’,5’-cyclic-gmp phosphodiesterase activity.
858	decreased 3’,5’-cyclic-amp phosphodiesterase activity. decreased 3’,5’-cyclic-gmp phosphodiesterase activity.
858	loss of 3’,5’-cyclic-amp phosphodiesterase activity. decreased 3’,5’-cyclic-gmp phosphodiesterase activity.
907	decreased 3’,5’-cyclic-amp phosphodiesterase activity. loss of 3’,5’-cyclic-gmp phosphodiesterase activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-418457	cGMP effects
R-HSA-418555	G alpha (s) signalling events

MSigDB gene sets: 0 (showing top):

GO Biological Process (27): negative regulation of transcription by RNA polymerase II (GO:0000122), heart valve development (GO:0003170), ventricular septum development (GO:0003281), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), positive regulation of gene expression (GO:0010628), negative regulation of receptor guanylyl cyclase signaling pathway (GO:0010754), regulation of mitochondrion organization (GO:0010821), obsolete cGMP-mediated signaling (GO:0019934), monocyte differentiation (GO:0030224), aorta development (GO:0035904), cellular response to macrophage colony-stimulating factor stimulus (GO:0036006), negative regulation of vascular permeability (GO:0043116), positive regulation of vascular permeability (GO:0043117), cGMP catabolic process (GO:0046069), positive regulation of inflammatory response (GO:0050729), establishment of endothelial barrier (GO:0061028), cellular response to mechanical stimulus (GO:0071260), cellular response to cAMP (GO:0071320), cellular response to cGMP (GO:0071321), cellular response to xenobiotic stimulus (GO:0071466), cellular response to transforming growth factor beta stimulus (GO:0071560), cellular response to granulocyte macrophage colony-stimulating factor stimulus (GO:0097011), negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0106072), negative regulation of cAMP/PKA signal transduction (GO:0141162), cellular response to 2,3,7,8-tetrachlorodibenzodioxine (GO:1904613), signal transduction (GO:0007165), obsolete regulation of cGMP-mediated signaling (GO:0010752)

GO Molecular Function (17): magnesium ion binding (GO:0000287), 3’,5’-cyclic-AMP phosphodiesterase activity (GO:0004115), 3’,5’-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity (GO:0004118), zinc ion binding (GO:0008270), cAMP binding (GO:0030552), cGMP binding (GO:0030553), TPR domain binding (GO:0030911), phosphate ion binding (GO:0042301), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), 3’,5’-cyclic-GMP phosphodiesterase activity (GO:0047555), nucleotide binding (GO:0000166), 3’,5’-cyclic-nucleotide phosphodiesterase activity (GO:0004114), protein binding (GO:0005515), phosphoric diester hydrolase activity (GO:0008081), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (14): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrial outer membrane (GO:0005741), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), presynaptic membrane (GO:0042734), perinuclear region of cytoplasm (GO:0048471), synaptic membrane (GO:0097060), mitochondrion (GO:0005739), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Nitric oxide stimulates guanylate cyclase	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	5
intracellular membrane-bounded organelle	4
cellular anatomical structure	4
3’,5’-cyclic-nucleotide phosphodiesterase activity	3
anion binding	3
regulation of vascular permeability	2
cellular response to nitrogen compound	2
cellular response to oxygen-containing compound	2
cyclic nucleotide binding	2
mitochondrial membrane	2
endomembrane system	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
heart development	1
anatomical structure development	1
cardiac ventricle development	1
cardiac septum development	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
receptor guanylyl cyclase signaling pathway	1
negative regulation of signal transduction	1
mitochondrion organization	1
regulation of organelle organization	1
myeloid leukocyte differentiation	1
mononuclear cell differentiation	1
artery development	1
response to macrophage colony-stimulating factor	1
cellular response to cytokine stimulus	1
purine ribonucleotide catabolic process	1
cyclic nucleotide catabolic process	1
cGMP metabolic process	1
inflammatory response	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
endothelial cell development	1

Protein interactions and networks

STRING

1126 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDE2A	ALDH7A1	P49419	669
PDE2A	PDE4A	P27815	555
PDE2A	PDE1B	Q01064	538
PDE2A	CYFIP2	Q96F07	482
PDE2A	ADCY5	O95622	475
PDE2A	OR4D2	P58180	399
PDE2A	ARAP1	Q96P48	391
PDE2A	PLD4	Q96BZ4	381
PDE2A	OR2Y1	Q8NGV0	376
PDE2A	PRKACA	P17612	368
PDE2A	B3GNT2	Q9NY97	366
PDE2A	RAPGEF3	O95398	365
PDE2A	PRKACB	P22694	364
PDE2A	PDE3A	Q14432	364
PDE2A	GUCY1B1	Q02153	363

IntAct

35 interactions, top by confidence:

A	B	Type	Score
AIP	PDE2A	psi-mi:“MI:0915”(physical association)	0.600
PDE2A	AIP	psi-mi:“MI:0915”(physical association)	0.600
PDE2A	AIP	psi-mi:“MI:0403”(colocalization)	0.600
NUFIP1	PDE2A	psi-mi:“MI:0914”(association)	0.530
ILVBL	SLC33A1	psi-mi:“MI:0914”(association)	0.530
KXD1	HIP1	psi-mi:“MI:0914”(association)	0.530
	PDE2A	psi-mi:“MI:0414”(enzymatic reaction)	0.440
		psi-mi:“MI:0914”(association)	0.350
NUFIP1	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.350
ACKR3	PDE2A	psi-mi:“MI:0914”(association)	0.350
FECH	POTEF	psi-mi:“MI:0914”(association)	0.350
BSCL2	QSOX1	psi-mi:“MI:0914”(association)	0.350
CXCL1	PDE2A	psi-mi:“MI:0914”(association)	0.350
DEFA5	PDE2A	psi-mi:“MI:0914”(association)	0.350
DHCR24	PDE2A	psi-mi:“MI:0914”(association)	0.350
FAF2	PDE2A	psi-mi:“MI:0914”(association)	0.350
FPR1	NBAS	psi-mi:“MI:0914”(association)	0.350
FZD10	PDE2A	psi-mi:“MI:0914”(association)	0.350
GPR17	C1QTNF9B	psi-mi:“MI:0914”(association)	0.350
HTR1E	ESYT2	psi-mi:“MI:0914”(association)	0.350
LPCAT4	PDE2A	psi-mi:“MI:0914”(association)	0.350
POMGNT2	FAM83G	psi-mi:“MI:0914”(association)	0.350
RIC3	QSOX1	psi-mi:“MI:0914”(association)	0.350
S1PR3	STXBP3	psi-mi:“MI:0914”(association)	0.350
UXS1	PDE2A	psi-mi:“MI:0914”(association)	0.350
VIPR2	SLC33A1	psi-mi:“MI:0914”(association)	0.350
CDH5	ESYT2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (122): PDE2A (Affinity Capture-RNA), PDE2A (Affinity Capture-RNA), PDE2A (Affinity Capture-MS), PDE2A (Affinity Capture-MS), PDE2A (Affinity Capture-MS), PDE2A (Affinity Capture-MS), IMMT (Affinity Capture-Western), CHCHD3 (Affinity Capture-Western), SAMM50 (Affinity Capture-Western), PDE2A (Affinity Capture-Western), PDE2A (Co-localization), PDE2A (Affinity Capture-Western), PDE2A (Affinity Capture-Western), IMMT (Affinity Capture-MS), SLC38A7 (Affinity Capture-MS)

ESM2 similar proteins: B3LVW5, B3P3K2, B4G4E5, B4HEM4, B4JXX2, B4K9L4, B4LVU6, B4NAL6, B4PSS5, B4QZU1, O00408, O54735, O60658, O76074, O77746, O88502, O95259, P0C1Q2, P11541, P14099, P16499, P16586, P23439, P23440, P27664, P33726, P35913, P51160, P52731, P91119, Q01062, Q07093, Q1KKS3, Q21029, Q28156, Q28263, Q298P4, Q3UYK3, Q60603, Q63472

Diamond homologs: B0G0Y8, B7YZV4, H2QL32, O00408, O08593, O18696, O70628, O76083, P06776, P14099, P14100, P54750, P70453, Q01061, Q01062, Q01064, Q01065, Q01066, Q13946, Q14123, Q1KKS3, Q23917, Q61481, Q63421, Q64338, Q64395, Q8I6Z7, Q8IKD3, Q8QZV1, Q922S4, Q9I7S6, Q9VJ79, B3LVW5, B3P3K2, B4G4E5, B4HEM4, B4JXX2, B4K9L4, B4LVU6, B4NAL6

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
caffeine	“down-regulates activity”	PDE2A	“chemical inhibition”
PDE2A	“down-regulates activity”	PRKACA	binding
PDE2A	“down-regulates activity”	PKA	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 35 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
G alpha (i) signalling events	6	9.3×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	3
Uncertain significance	147
Likely benign	166
Benign	25

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
2217721	NM_002599.5(PDE2A):c.574_592dup (p.Gly198fs)	Pathogenic
689477	NM_002599.5(PDE2A):c.1180C>T (p.Gln394Ter)	Pathogenic
995830	NM_002599.5(PDE2A):c.1922+5G>A	Pathogenic
995831	NM_002599.5(PDE2A):c.446C>T (p.Pro149Leu)	Pathogenic
995832	NM_002599.5(PDE2A):c.323+1G>A	Pathogenic
1696651	NM_002599.5(PDE2A):c.2134-2A>G	Likely pathogenic
3337442	NM_002599.5(PDE2A):c.2256+1G>A	Likely pathogenic
3337443	NM_002599.5(PDE2A):c.2123A>C (p.Gln708Pro)	Likely pathogenic

SpliceAI

5768 predictions. Top by Δscore:

Variant	Effect	Δscore
11:72577590:ACAGC:A	acceptor_gain	1.0000
11:72577591:CAGC:C	acceptor_gain	1.0000
11:72577591:CAGCC:C	acceptor_gain	1.0000
11:72577593:GC:G	acceptor_gain	1.0000
11:72577594:CC:C	acceptor_gain	1.0000
11:72577595:C:CC	acceptor_gain	1.0000
11:72577598:CGGG:C	acceptor_gain	1.0000
11:72577601:G:C	acceptor_gain	1.0000
11:72577601:G:GC	acceptor_gain	1.0000
11:72577604:CA:C	acceptor_gain	1.0000
11:72577605:A:AC	acceptor_gain	1.0000
11:72577605:A:C	acceptor_gain	1.0000
11:72578227:A:AC	donor_gain	1.0000
11:72578228:C:CC	donor_gain	1.0000
11:72578228:CTCA:C	donor_gain	1.0000
11:72578229:TCAC:T	donor_loss	1.0000
11:72578230:CA:C	donor_loss	1.0000
11:72578231:A:AC	donor_gain	1.0000
11:72578232:C:CC	donor_gain	1.0000
11:72578340:C:CC	acceptor_gain	1.0000
11:72578893:CTA:C	donor_loss	1.0000
11:72578894:TACCG:T	donor_loss	1.0000
11:72578895:A:AC	donor_gain	1.0000
11:72578896:C:CA	donor_loss	1.0000
11:72578896:C:CC	donor_gain	1.0000
11:72578896:CCG:C	donor_gain	1.0000
11:72579005:GCCCA:G	acceptor_gain	1.0000
11:72579006:CCCA:C	acceptor_gain	1.0000
11:72579006:CCCAC:C	acceptor_gain	1.0000
11:72579007:CCA:C	acceptor_gain	1.0000

AlphaMissense

6244 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:72577525:C:A	W895C	1.000
11:72577525:C:G	W895C	1.000
11:72577526:C:G	W895S	1.000
11:72577527:A:G	W895R	1.000
11:72577527:A:T	W895R	1.000
11:72578248:G:T	A867E	1.000
11:72578262:G:C	F862L	1.000
11:72578262:G:T	F862L	1.000
11:72578263:A:C	F862C	1.000
11:72578263:A:G	F862S	1.000
11:72578264:A:C	F862V	1.000
11:72578264:A:G	F862L	1.000
11:72578264:A:T	F862I	1.000
11:72578271:T:A	Q859H	1.000
11:72578271:T:G	Q859H	1.000
11:72578272:T:G	Q859P	1.000
11:72578275:A:G	L858P	1.000
11:72578281:G:T	P856H	1.000
11:72578284:A:C	I855S	1.000
11:72578284:A:G	I855T	1.000
11:72578284:A:T	I855N	1.000
11:72578290:G:T	A853D	1.000
11:72578299:C:A	R850L	1.000
11:72578299:C:G	R850P	1.000
11:72578300:G:C	R850G	1.000
11:72578302:T:G	D849A	1.000
11:72578303:C:G	D849H	1.000
11:72578304:C:A	M848I	1.000
11:72578304:C:G	M848I	1.000
11:72578304:C:T	M848I	1.000

dbSNP variants (sampled 300 via entrez): RS1000004817 (11:72639031 C>A,T), RS1000030403 (11:72586274 G>A,T), RS1000123112 (11:72673619 A>G,T), RS1000123566 (11:72632188 A>G), RS1000201242 (11:72650055 C>G,T), RS1000209237 (11:72587946 C>T), RS1000210862 (11:72594227 A>G), RS1000219799 (11:72673235 T>C), RS1000229066 (11:72611625 A>C), RS1000284507 (11:72592456 C>T), RS1000309456 (11:72591233 C>T), RS1000313947 (11:72599363 C>T), RS1000335401 (11:72578735 C>T), RS1000363246 (11:72625957 T>C), RS1000405640 (11:72586588 C>T)

Disease associations

OMIM: gene MIM:602658 | disease phenotypes: MIM:619150

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual developmental disorder with paroxysmal dyskinesia or seizures	Strong	Autosomal recessive
infantile convulsions and choreoathetosis	Supportive	Autosomal dominant

Mondo (4): intellectual developmental disorder with paroxysmal dyskinesia or seizures (MONDO:0030900), choreatic disease (MONDO:0001595), paroxysmal dystonia (MONDO:0016058), infantile convulsions and choreoathetosis (MONDO:0011178)

Orphanet (2): Benign hereditary chorea (Orphanet:1429), Paroxysmal dystonia (Orphanet:200037)

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000273	Facial grimacing
HP:0000718	Aggressive behavior
HP:0000733	Motor stereotypy
HP:0000748	Inappropriate laughter
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0001332	Dystonia
HP:0002072	Chorea
HP:0002119	Ventriculomegaly
HP:0002311	Incoordination
HP:0002342	Moderate intellectual disability
HP:0002353	EEG abnormality
HP:0002376	Developmental regression
HP:0002527	Falls
HP:0003593	Infantile onset
HP:0003763	Bruxism
HP:0007166	Paroxysmal dyskinesia
HP:0007359	Focal-onset seizure
HP:0008936	Axial hypotonia
HP:0032663	Focal motor status epilepticus
HP:0100785	Insomnia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000659_6	Optic nerve measurement (cup area)	5.000000e-06
GCST001454_7	Rheumatoid arthritis	6.000000e-10
GCST009524_89	Household income (MTAG)	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009695	household income

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002819	Chorea	C10.228.662.262.249; C10.597.350.250; C23.888.592.350.250
C535522	Infantile convulsions and paroxysmal choreoathetosis, familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2111470 (SELECTIVITY GROUP), CHEMBL2363066 (PROTEIN FAMILY), CHEMBL2652 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

12 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 208,709 (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
CHEMBL1520	VARDENAFIL	4	21,078
CHEMBL1750	CLOFARABINE	4	31,786
CHEMBL192	SILDENAFIL	4	41,819
CHEMBL760	ANAGRELIDE	4	23,754
CHEMBL932	DIPYRIDAMOLE	4	51,743
CHEMBL19224	PAPAVERINE	3	22,172
CHEMBL150764	BUFROLIN	2	131
CHEMBL28079	ZAPRINAST	2	16,158
CHEMBL2180408	JNJ-42396302	1	12
CHEMBL3092562	PF-05180999	1	28
CHEMBL3770459	LENRISPODUN PHOSPHATE	1	14
CHEMBL4060569	TAK-915	1	14

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Phosphodiesterases, 3’,5’-cyclic nucleotide (PDEs)

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
PF-05180999	Inhibition	8.8	pIC50
BAY607550	Inhibition	8.8	pIC50
milrinone	Inhibition	6.52	pIC50
EHNA	Inhibition	5.3	pIC50

Binding affinities (BindingDB)

1025 measured of 1192 human assays (1667 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(R)- or (S)-1- (Cyclopropyl(4-(1,1- difluoroethyl)-3- fluorophenyl)methyl)- 6-(dimethylamino)-3- (hydroxymethyl)-1H- pyrazolo[3,4- d]pyrimidin-4(5H)-one	KI	0.02 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
(R)- or (S)-6-(Dimethylamino)-1-(1-(2- fluoro-4-(trifluoromethyl)phenyl)-2- methylpropyl)-3-(fluoromethyl)-1H- pyrazolo[3,4-d]pyrimidin-4(5H)-one	KI	0.041 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
(R)- or (S)-6-(Dimethylamino)-1-(1-(3- fluoro-4-(trifluoromethyl)phenyl)propyl)-3- (fluoromethyl)-1H-pyrazolo[3,4- d]pyrimidin-4(5H)-one	KI	0.044 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
(R)- or (S)-1-(1-(4-(1,1-Difluoroethyl)-2- fluorophenyl)propyl)-6-(dimethylamino)-3- (fluoromethyl)-1H-pyrazolo[3,4- d]pyrimidin-4(5H)-one	KI	0.045 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
(R)- or (S)-6-(Dimethylamino)-1-(1-(2- fluoro-4-(trifluoromethyl)phenyl)propyl)-3- (fluoromethyl)-1H-pyrazolo[3,4- d]pyrimidin-4(5H)-one	KI	0.048 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
(R)- or (S)-1- (Cyclopropyl(4-(1,1- difluoroethyl)-2- fluorophenyl)methyl)- 6-(dimethylamino)-3- (hydroxymethyl)-1H- pyrazolo[3,4- d]pyrimidin-4(5H)-one	KI	0.05 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
(R)- or (S)-6-(Dimethylamino)- 1-(1-(2-fluoro-4- (trifluoromethyl)phenyl)propyl)- 3-(hydroxymethyl)-1H- pyrazolo[3,4-d]pyrimidin- 4(5H)-one	KI	0.071 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
2-(dimethylamino)-N-{(1S)-2- hydroxy-2-methyl-1-[4- (pentafluoro-lambda6- sulfanyl)phenyl]propyl}-6-oxo- 1,6-dihydropyrimidine-4- carboxamide	KI	0.073 nM	US-10285989: Pyrimidinone amide compounds as PDE2 inhibitors
(R)- or (S)-1-(1-(4- (Difluoromethyl)phenyl) propyl)-6-(dimethylamino)- 3-(fluoromethyl)-1H- pyrazolo[3,4- d]pyrimidin-4(5H)-one	KI	0.08 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
N-{(1R)-2,2-dimethyl-1-[4- (trifluoromethyl)phenyl]propyl}-2- [(3S)-3- methoxypyrrolidin-1-yl]-6-oxo-1,6- dihydropyrimidine-4-carboxamide	KI	0.11 nM	US-10285989: Pyrimidinone amide compounds as PDE2 inhibitors
2-(dimethylamino)-N-{(1S)-1-[3- fluoro-4- (trifluoromethoxy)phenyl]-2- hydroxy-2-methylpropyl}-6-oxo- 1,6-dihydropyrimidine-4- carboxamide	KI	0.12 nM	US-10285989: Pyrimidinone amide compounds as PDE2 inhibitors
(R)- or (S)-6-(Dimethylamino)-1-(1-(2- fluoro-4-(trifluoromethyl)phenyl)ethyl)-3- (fluoromethyl)-1H-pyrazolo[3,4- d]pyrimidin-4(5H)-one	KI	0.13 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
(R)- or (S)-1-(1-(4- (Difluoromethyl)-3- fluorophenyl)propyl)- 6-(dimethylamino)-3- (fluoromethyl)-1H- pyrazolo[3,4- d]pyrimidin-4(5H)- one	KI	0.13 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
(R)- or (S)-1-(1-(4- (Difluoromethoxy)-3- fluorophenyl)propyl)- 6-(dimethylamino)-3- (fluoromethyl)-1H- pyrazolo[3,4- d]pyrimidin-4(5H)- one	KI	0.15 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
3-(Fluoromethyl)-6-pyrrolidin-1-yl-1- {(1S)-1-[4- (trifluoromethyl)phenyl]ethyl}-1,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin- 4-one	KI	0.22 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
(R)- or (S)-1-(1-(4-(1,1- DiHuoroethyl)-2-fluoroplienyl)ethyl)- 6-(dimethylamino)-3- (hydroxymethyl)-1H-pyrazolo[3,4- d]pyrimidin-4(5H)-one	KI	0.23 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
3-(difluoromethyl)-6-(dimethylamino)-1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]-3,3a,5,6,7,7a-hexahydro-2H-pyrazolo[3,4-d]pyrimidin-4-one	KI	0.25 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
6-(azetidin-1-yl)-3-(difluoromethyl)-1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]-3,3a,5,6,7,7a-hexahydro-2H-pyrazolo[3,4-d]pyrimidin-4-one	KI	0.26 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
1-[(S)-cyclopropyl-[4-(difluoromethyl)phenyl]methyl]-6-(dimethylamino)-3-(hydroxymethyl)-3,3a,5,6,7,7a-hexahydro-2H-pyrazolo[3,4-d]pyrimidin-4-one	KI	0.27 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
4-(azetidin-1-yl)-7-methyl-5-[1-methyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]imidazo[5,1-f][1,2,4]triazine	IC50	0.303 nM	US-8598155: Imidazo[5,1-f][1,2,4]triazines for the treatment of neurological disorders
(R)- or (S)-1-(1-(4-(Difluoromethyl)-3- fluorophenyl)ethyl)-6-(dimethylamino)-3- (fluoromethyl)-1H-pyrazolo[3,4- d]pyrimidin-4(5H)-one	KI	0.31 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
1-[(1S)-1-[4-(1,1-difluoroethyl)phenyl]-2-methylpropyl]-3-(hydroxymethyl)-6-(methylamino)-3,3a,5,6,7,7a-hexahydro-2H-pyrazolo[3,4-d]pyrimidin-4-one	KI	0.33 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
(R)- or (S)-N-{(1R)-2,2- dimethyl-1-[4- (trifluoromethyl)phenyl] propyl}-2-[3-(methoxy- methyl)pyrrolidin-1-yl]- 6-oxo-1,6-dihydro- pyrimidine-4-carboxamide	KI	0.38 nM	US-10285989: Pyrimidinone amide compounds as PDE2 inhibitors
N-{(1R)-1-[4-(1,1- difluoroethyl)phenyl]-2- methylpropyl}-2-(dimethylamino)-6- oxo-1,6-dihydropyrimidine-4- carboxamide	KI	0.39 nM	US-10285989: Pyrimidinone amide compounds as PDE2 inhibitors
5-(hydroxymethyl)-2-methyl-7-[1-[4-(1-methylcyclopropyl)phenyl]ethyl]-2,3-dihydro-1H-imidazo[5,1-f][1,2,4]triazin-4-one	KI	0.4 nM	US-10287293: Bicyclic heterocyclic compounds as PDE2 inhibitors
6-Azetidin-1-yl-3-(fluoromethyl)-1- {(1S)-1-[4- (trifluoromethyl)phenyl]ethyl}-1,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin- 4-one	KI	0.41 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
6-[4-[(1S)-1-[2-chloro-4-(trifluoromethyl)phenyl]ethyl]triazol-1-yl]-2-methyl-1,3-diazinan-4-one	KI	0.42 nM	US-10358435: Triazolyl pyrimidinone compounds as PDE2 inhibitors
N-{(1R)-2,2-dimethyl-1-[4- (trifluoromethoxy)phenyl]propyl}- 2-(4-methoxybenzyl)-6-oxo-1,6- dihydropyrimidine-4-carboxamide	KI	0.49 nM	US-9815796: Pyrimidone carboxamide compounds as PDE2 inhibitors
2-fluoro-4-[3-[1-(7-fluoroquinolin-2-yl)azetidin-3-yl]pyrazin-2-yl]-N-methylbenzamide	IC50	0.5 nM	US-8691986: Azetidine and piperidine compounds useful as PDE10 inhibitors
N-[(2S)-2-[2-chloro-4-(trifluoromethyl)phenyl]-1-hydroxypropan-2-yl]-6-oxo-2-phenyl-1,3-diazinane-4-carboxamide	KI	0.5 nM	US-9815796: Pyrimidone carboxamide compounds as PDE2 inhibitors
N-[(1R)-1-(4-cyclopropylphenyl)-2,2-dimethylpropyl]-6-oxo-2-phenyl-1,3-diazinane-4-carboxamide	KI	0.51 nM	US-9815796: Pyrimidone carboxamide compounds as PDE2 inhibitors
4-(azetidin-1-yl)-5-[5-(4-ethylphenyl)-1-methylpyrazol-4-yl]-7-methylimidazo[5,1-f][1,2,4]triazine	IC50	0.517 nM	US-8598155: Imidazo[5,1-f][1,2,4]triazines for the treatment of neurological disorders
2-Methyl-2-(1H-pyrazol-1-yl)propanimidamide acetate	KI	0.52 nM	US-9815796: Pyrimidone carboxamide compounds as PDE2 inhibitors
N-{(1S)-1-[2-chloro-4- (trifluoromethyl)phenyl]-2- hydroxy-1-methylethyl}-2- (dimethylamino)-6-oxo-1,6- dihydropyrimidine-4-carboxamide	KI	0.52 nM	US-10285989: Pyrimidinone amide compounds as PDE2 inhibitors
N-{(1S)-1-[2-chloro-4- (trifluoromethoxy)phenyl]-2- hydroxy-2-methylpropyl}-2- (dimethylamino)-6-oxo- 1,6-dihydropyrimidine-4- carboxamide	KI	0.54 nM	US-10285989: Pyrimidinone amide compounds as PDE2 inhibitors
6-[7-[2-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-5,6-dihydro-4H-triazolo[1,5-a]pyridin-3-yl]-2-[(3-methoxyphenyl)methyl]-1,3-diazinan-4-one	KI	0.56 nM	US-10358435: Triazolyl pyrimidinone compounds as PDE2 inhibitors
(R)- or (S)-1-(Cyclopropyl(4- (difluoromethyl)-3- fluorophenyl)methyl)-6- (dimethylamino)-3-(hydroxymethyl)- 1H-pyrazolo[3,4-d]pyrimidin-4(5H)- one	KI	0.57 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
4-(azetidin-1-yl)-5-[5-(4-methoxy-2-methylphenyl)-1-methylpyrazol-4-yl]-7-methylimidazo[5,1-f][1,2,4]triazine	IC50	0.578 nM	US-8598155: Imidazo[5,1-f][1,2,4]triazines for the treatment of neurological disorders
N-{(1R)-2,2-dimethyl-1-[4- (trifluoromethyl)phenyl]propyl}-2- (4-methoxybenzyl)-6-oxo-1,6- dihydropyrimidine-4-carboxamide	KI	0.6 nM	US-9815796: Pyrimidone carboxamide compounds as PDE2 inhibitors
N-[(1R)-2,2-dimethyl-1-{4- [(trifluoromethyl)sulfanyl]phenyl} propyl]-2-(4-methoxybenzyl)-6-oxo- 1,6-dihydropyrimidine-4- carboxamide	KI	0.62 nM	US-9815796: Pyrimidone carboxamide compounds as PDE2 inhibitors
4-(3-fluoroazetidin-1-yl)-7-methyl-5-[1-methyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]imidazo[5,1-f][1,2,4]triazine	IC50	0.633 nM	US-8598155: Imidazo[5,1-f][1,2,4]triazines for the treatment of neurological disorders
N-{(1R)-2,2-dimethyl-1-[4- (trifluoromethyl)phenyl]propyl}-2- (3-fluoro-4-methoxybenzyl)-6-oxo- 1,6-dihydropyrimidine-4- carboxamide	KI	0.64 nM	US-9815796: Pyrimidone carboxamide compounds as PDE2 inhibitors
N-{(1R)-1-[3-fluoro-4- (trifluoromethoxy)phenyl]-2,2- dimethylpropyl}-2-(4- methoxybenzyl)-6-oxo-1,6- dihydropyrimidine-4-carboxamide	KI	0.69 nM	US-9815796: Pyrimidone carboxamide compounds as PDE2 inhibitors
N-methyl-3-[3-(1-quinolin-2-ylazetidin-3-yl)pyrazin-2-yl]benzamide	IC50	0.7 nM	US-8957073: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
(R)- or (S)-1-(1-(4- (Difluoromethoxy)phenyl) propyl)-6-(dimethylamino)-3- (hydroxymethyl)-1H- pyrazolo[3,4-d]pyrimidin- 4(5H)-one	KI	0.73 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
4-(azetidin-1-yl)-5-[5-(2-chloro-4-methoxyphenyl)-1-methylpyrazol-4-yl]-7-methylimidazo[5,1-f][1,2,4]triazine	IC50	0.761 nM	US-8598155: Imidazo[5,1-f][1,2,4]triazines for the treatment of neurological disorders
[4-(methylamino)-5-[1-methyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]imidazo[5,1-f][1,2,4]triazin-7-yl]methanol	IC50	0.763 nM	US-8598155: Imidazo[5,1-f][1,2,4]triazines for the treatment of neurological disorders
2-cyclopropyl-N-[(1R)-1-(4- cyclopropyl-3-fluorophenyl)-2,2- dimethylpropyl]-6-oxo-1,6- dihydropyrimidine-4-carboxamide	KI	0.78 nM	US-9815796: Pyrimidone carboxamide compounds as PDE2 inhibitors
N-{(1R)-1-[3-fluoro-4- (trifluoromethyl)phenyl]-2,2- dimethylpropyl}-2-(4- methoxybenzyl)-6-oxo-1,6- dihydropyrimidine-4-carboxamide	KI	0.79 nM	US-9815796: Pyrimidone carboxamide compounds as PDE2 inhibitors
2-(3-fluoro-4-methoxybenzyl)-N- {(1R)-1-[3-fluoro-4- (trifluoromethoxy)phenyl]-2,2- dimethylpropyl}-6-oxo-1,6- dihydropyrimidine-4-carboxamide	KI	0.8 nM	US-9815796: Pyrimidone carboxamide compounds as PDE2 inhibitors

ChEMBL bioactivities

3698 potent at pChembl≥5 of 3803 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.80	Ki	0.016	nM	CHEMBL5827044
10.77	Ki	0.017	nM	CHEMBL5773913
10.70	Ki	0.02	nM	CHEMBL6019094
10.66	Ki	0.022	nM	CHEMBL5867733
10.62	Ki	0.024	nM	CHEMBL6027642
10.52	IC50	0.03	nM	CHEMBL370962
10.52	Ki	0.03	nM	CHEMBL5948981
10.52	Ki	0.03	nM	CHEMBL6040588
10.52	Ki	0.03	nM	CHEMBL5847109
10.42	Ki	0.038	nM	CHEMBL6032923
10.40	Ki	0.04	nM	CHEMBL6028983
10.39	Ki	0.041	nM	CHEMBL5774777
10.38	Ki	0.042	nM	CHEMBL5880032
10.36	Ki	0.044	nM	CHEMBL6045656
10.36	Ki	0.044	nM	CHEMBL5871807
10.35	Ki	0.045	nM	CHEMBL5827382
10.34	Ki	0.046	nM	CHEMBL5771360
10.33	Ki	0.047	nM	CHEMBL5912514
10.33	Ki	0.047	nM	CHEMBL5869948
10.32	Ki	0.048	nM	CHEMBL6050934
10.32	Ki	0.048	nM	CHEMBL6032101
10.30	Ki	0.05	nM	CHEMBL5886652
10.28	Ki	0.053	nM	CHEMBL5748229
10.25	Ki	0.056	nM	CHEMBL5963263
10.24	Ki	0.057	nM	CHEMBL6047592
10.24	Ki	0.058	nM	CHEMBL5937033
10.22	IC50	0.06	nM	CHEMBL4071033
10.20	Ki	0.063	nM	CHEMBL5866384
10.19	Ki	0.064	nM	CHEMBL5899608
10.19	Ki	0.064	nM	CHEMBL5788813
10.17	Ki	0.068	nM	CHEMBL5773913
10.16	Ki	0.069	nM	CHEMBL5928367
10.16	Ki	0.069	nM	CHEMBL6057847
10.15	Ki	0.071	nM	CHEMBL5952104
10.15	Ki	0.07	nM	CHEMBL5906907
10.14	Ki	0.073	nM	CHEMBL6029400
10.14	Ki	0.072	nM	CHEMBL5938025
10.14	Ki	0.073	nM	CHEMBL5808459
10.11	Ki	0.077	nM	CHEMBL5851735
10.10	Ki	0.08	nM	CHEMBL5988705
10.05	Ki	0.09	nM	CHEMBL5755097
10.00	IC50	0.1	nM	CHEMBL5081214
10.00	Ki	0.099	nM	CHEMBL5893408
10.00	Ki	0.1	nM	CHEMBL5963424
9.96	Ki	0.11	nM	CHEMBL6045656
9.96	Ki	0.11	nM	CHEMBL6047592
9.96	Ki	0.11	nM	CHEMBL5744255
9.96	Ki	0.11	nM	CHEMBL5842060
9.92	Ki	0.12	nM	CHEMBL6023089
9.92	Ki	0.12	nM	CHEMBL6048289

PubChem BioAssay actives

657 with measured affinity, of 1465 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
2-[(3,4-dimethoxyphenyl)methyl]-7-[(2R,3R)-2-hydroxy-6-phenylhexan-3-yl]-5-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1480122: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	<0.0001	uM
5-(difluoromethyl)-7-[1,3-dimethyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-2-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1480122: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]sulfamoyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-[[N-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxycarbonyl]anilino]methyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0001	uM
7-[1,3-dimethyl-5-[3-methyl-4-(trifluoromethyl)phenyl]pyrazol-4-yl]-5-(hydroxymethyl)-2-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1480122: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0002	uM
7-[1,3-dimethyl-5-[3-methyl-4-(trifluoromethyl)phenyl]pyrazol-4-yl]-2,5-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1480122: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0002	uM
5-(difluoromethyl)-2-methyl-7-[5-methyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1480122: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0002	uM
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]amino]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0002	uM
7-[1,3-dimethyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-5-(hydroxymethyl)-2-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1480122: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0003	uM
4-(azetidin-1-yl)-7-methyl-5-[1-methyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]imidazo[5,1-f][1,2,4]triazine	1472968: Inhibition of full length human N-terminal FLAG-tagged PDE2A3 expressed in sf21 cells using [3H]cGMP as substrate after 30 mins by SPA	ic50	0.0003	uM
1-(2,6-dichlorophenyl)-N-ethyl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide	724277: Inhibition of human recombinant PDE2A expressed in Sf9 cells by scintillation proximity assay	ic50	0.0003	uM
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]amino]methyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0003	uM
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]sulfamoyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0003	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-[[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]amino]methyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0003	uM
N-benzyl-1-(2-chlorophenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide	724277: Inhibition of human recombinant PDE2A expressed in Sf9 cells by scintillation proximity assay	ic50	0.0004	uM
1-(2-chlorophenyl)-4-methyl-N-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide	724277: Inhibition of human recombinant PDE2A expressed in Sf9 cells by scintillation proximity assay	ic50	0.0004	uM
4-(3-fluoroazetidin-1-yl)-7-methyl-5-[1-methyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]imidazo[5,1-f][1,2,4]triazine	747976: Inhibition of full length recombinant human PDE2A expressed in Sf21 cells using [3H]-cGMP as substrate by scintillation proximity assay	ic50	0.0005	uM
1-(2-chlorophenyl)-4-methyl-N-(2-morpholin-4-ylethyl)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide	724277: Inhibition of human recombinant PDE2A expressed in Sf9 cells by scintillation proximity assay	ic50	0.0005	uM
N-[(1S)-2-hydroxy-2-methyl-1-[4-(trifluoromethoxy)phenyl]propyl]-6-methyl-5-(3-methyl-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide	1923556: Inhibition of PDE2A (unknown origin)	ic50	0.0005	uM
7-[1,3-dimethyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-2,5-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1350143: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate measured after 30 mins by Yttrium silicate scintillation proximity assay	ic50	0.0006	uM
1-benzofuran-5-yl-[(3S,4R)-3-[5-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]-4-methylpiperidin-1-yl]methanone	1678216: Inhibition of 6xHis-tagged human recombinant PDE2A expressed in Sf9 cells in presence of [3H]-cGMP and cGMP incubated for 40 mins by scintillation counting method	ic50	0.0006	uM
4-(azetidin-1-yl)-5-[5-(4-methoxy-2-methylphenyl)-1-methylpyrazol-4-yl]-7-methylimidazo[5,1-f][1,2,4]triazine	747976: Inhibition of full length recombinant human PDE2A expressed in Sf21 cells using [3H]-cGMP as substrate by scintillation proximity assay	ic50	0.0006	uM
1-(2-chlorophenyl)-N-ethyl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide	724277: Inhibition of human recombinant PDE2A expressed in Sf9 cells by scintillation proximity assay	ic50	0.0006	uM
N-[(1S)-1-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl]-7-methoxy-2-oxo-1,3-dihydropyrido[2,3-b]pyrazine-4-carboxamide	1458906: Inhibition of recombinant human full-length His-tagged PDE2A3 expressed in fall armyworm Sf9 cells using [3H]cGMP as substrate preincubated for 30 mins followed by substrate addition measured after 60 mins by scintillation counting	ic50	0.0006	uM
[(3S)-3-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl]-naphthalen-2-ylmethanone	1440918: Inhibition of human full length GST-tagged PDE2a using FAM-labeled cAMP as substrate preincubated for 5 mins followed by substrate addition measured after 30 mins by IMAP assay	ic50	0.0008	uM
4-(azetidin-1-yl)-5-[5-(2-fluoro-4-methoxyphenyl)-1-methylpyrazol-4-yl]-7-methylimidazo[5,1-f][1,2,4]triazine	747976: Inhibition of full length recombinant human PDE2A expressed in Sf21 cells using [3H]-cGMP as substrate by scintillation proximity assay	ic50	0.0008	uM
1-(2-fluoroethyl)-3-[(1R)-1-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-5-methyl-6H-pyrazolo[4,5-d]pyrimidin-7-one	1776789: Inhibition of human PDE2	ki	0.0009	uM
7-[5-(4-chlorophenyl)-1,3-dimethylpyrazol-4-yl]-5-(hydroxymethyl)-2-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1480122: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0009	uM
3-(8-methoxy-1-methyl-2-oxo-7-phenyl-3H-1,4-benzodiazepin-5-yl)benzamide	1924473: Inhibition of PDE2A (unknown origin)	ic50	0.0010	uM
[3-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl]-naphthalen-2-ylmethanone	1440918: Inhibition of human full length GST-tagged PDE2a using FAM-labeled cAMP as substrate preincubated for 5 mins followed by substrate addition measured after 30 mins by IMAP assay	ic50	0.0010	uM
[3,3-difluoro-5-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl]-naphthalen-2-ylmethanone	1440918: Inhibition of human full length GST-tagged PDE2a using FAM-labeled cAMP as substrate preincubated for 5 mins followed by substrate addition measured after 30 mins by IMAP assay	ic50	0.0010	uM
5-(difluoromethyl)-7-[3-(hydroxymethyl)-1-methyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-2-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1480122: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0010	uM
(3S)-1-[7-methyl-5-[1-methyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]imidazo[5,1-f][1,2,4]triazin-4-yl]pyrrolidine-3-carboxylic acid	1411989: Inhibition of PDE2A (unknown origin)	ic50	0.0010	uM
4-(azetidin-1-yl)-7-methyl-5-[1-methyl-5-[5-(trifluoromethyl)-2-pyridinyl]pyrazol-4-yl]imidazo[5,1-f][1,2,4]triazine	1058003: Inhibition of recombinant human full length PDE2A3 expressed in insect SF-21 cells using [3H]-cGMP as substrate by scintillation proximity assay	ic50	0.0010	uM
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[N-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxycarbonyl]anilino]methyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0010	uM
4-[[1-(2-chloro-6-(18F)fluorophenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl]methyl]morpholine	1057995: Inhibition of recombinant human PDE2A expressed in baculovirus infected insect SF9 cells using [3H]-cGMP as substrate after 45 mins by scintillation proximity assay	ic50	0.0010	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]amino]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0010	uM
3-[(1R)-1-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-1-(2-hydroxyethyl)-5-methyl-6H-pyrazolo[4,5-d]pyrimidin-7-one	1776789: Inhibition of human PDE2	ki	0.0011	uM
5-(hydroxymethyl)-2-methyl-7-[5-methyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1480122: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0011	uM
1-benzofuran-5-yl-[3-[5-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]-4-methylpiperidin-1-yl]methanone	1678216: Inhibition of 6xHis-tagged human recombinant PDE2A expressed in Sf9 cells in presence of [3H]-cGMP and cGMP incubated for 40 mins by scintillation counting method	ic50	0.0011	uM
4-(azetidin-1-yl)-5-[5-(2,3-difluoro-4-methoxyphenyl)-1-methylpyrazol-4-yl]-7-methylimidazo[5,1-f][1,2,4]triazine	747976: Inhibition of full length recombinant human PDE2A expressed in Sf21 cells using [3H]-cGMP as substrate by scintillation proximity assay	ic50	0.0011	uM
3-tert-butyl-1-(2-hydroxyethyl)-5-[4-methoxy-3-(2-pyrrolidin-1-ylpyrimidin-5-yl)phenyl]-6,7-dihydropyrazolo[4,5-e][1,4]diazepin-8-one	749038: Inhibition of PDE2 catalytic domain (unknown origin)	ic50	0.0012	uM
3-[(1S)-1-(4-tert-butylphenyl)ethyl]-1-(2-fluoroethyl)-5-methyl-6H-pyrazolo[4,5-d]pyrimidin-7-one	2124203: Inhibition of PDE2A (unknown origin) using 3H-cGMP as substrate	ic50	0.0013	uM
3-[(1R)-1-(4-tert-butylphenyl)ethyl]-1-(2-fluoroethyl)-5-methyl-6H-pyrazolo[4,5-d]pyrimidin-7-one	1776789: Inhibition of human PDE2	ki	0.0013	uM
7-methyl-5-[1-methyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]imidazo[5,1-f][1,2,4]triazin-4-amine	1472968: Inhibition of full length human N-terminal FLAG-tagged PDE2A3 expressed in sf21 cells using [3H]cGMP as substrate after 30 mins by SPA	ic50	0.0013	uM
5-(difluoromethyl)-7-[(3S,4R)-4-methyl-1-(4-phenyl-2-pyridinyl)piperidin-3-yl]-[1,2,4]triazolo[1,5-a]pyrimidine	1678216: Inhibition of 6xHis-tagged human recombinant PDE2A expressed in Sf9 cells in presence of [3H]-cGMP and cGMP incubated for 40 mins by scintillation counting method	ic50	0.0013	uM
3-tert-butyl-5-[3-[6-(dimethylamino)-4-methyl-3-pyridinyl]-4-methoxyphenyl]-1-(2-hydroxyethyl)-6,7-dihydropyrazolo[4,5-e][1,4]diazepin-8-one	749038: Inhibition of PDE2 catalytic domain (unknown origin)	ic50	0.0013	uM
1-(2-chlorophenyl)-N-[2-(diethylamino)ethyl]-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide	724277: Inhibition of human recombinant PDE2A expressed in Sf9 cells by scintillation proximity assay	ic50	0.0014	uM
3-tert-butyl-1-(2-hydroxyethyl)-5-[4-methoxy-3-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6,7-dihydropyrazolo[4,5-e][1,4]diazepin-8-one	749038: Inhibition of PDE2 catalytic domain (unknown origin)	ic50	0.0014	uM
(1-methylsulfonylindol-5-yl)-[(3S)-3-([1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl]methanone	1678216: Inhibition of 6xHis-tagged human recombinant PDE2A expressed in Sf9 cells in presence of [3H]-cGMP and cGMP incubated for 40 mins by scintillation counting method	ic50	0.0015	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	3
Aflatoxin B1	increases expression, affects methylation	3
bisphenol A	affects cotreatment, increases methylation, decreases expression	2
sulindac sulfone	affects binding, decreases activity	2
Resveratrol	decreases expression	2
Vorinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	2
Nickel	decreases expression	2
Cyclosporine	increases expression	2
TAK-243	increases sumoylation	1
Esketamine	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
methylmercuric chloride	decreases expression	1
propionaldehyde	increases expression	1
titanium dioxide	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	affects methylation	1
pentanal	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
seocalcitol	increases expression	1
CGP 52608	affects binding, increases reaction	1
4,5-dimethoxy-2-nitrobenzyl-8-bromo-cAMP	affects localization, decreases reaction	1
(5-fluoro-2-methyl-1-(4-pyridyl)methylene-3-(N-benzyl)-indene)-acetamide hydrochloride	affects binding, decreases activity	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	increases expression	1
quinocetone	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1

ChEMBL screening assays

346 unique, capped per target: 331 binding, 8 admet, 7 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4373090	Binding	Selectivity ratio of IC50 for PDE5 (unknown origin) to IC50 for PDE2 (unknown origin)	Design, synthesis of novel purin-6-one derivatives as phosphodiesterase 2 (PDE2) inhibitors: The neuroprotective and anxiolytic-like effects. — Bioorg Med Chem Lett
CHEMBL4680008	ADMET	Inhibition of PDE (unknown origin)	Fragment-Based Discovery of Novel Allosteric MEK1 Binders. — ACS Med Chem Lett
CHEMBL5723181	Functional	Affinity Biochemical interaction: (inhibition of enzyme activity with [3H]cGMP or [3H]cAMP as the substrate) EUB0002477a PDE2A	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C0TI	ACTOne cAMP-PDE2A	Transformed cell line	Female

Clinical trials (associated diseases)

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