PDE5A

Summary

PDE5A (phosphodiesterase 5A, HGNC:8784) is a protein-coding gene on chromosome 4q26, encoding cGMP-specific 3’,5’-cyclic phosphodiesterase (O76074). Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides.

This gene encodes a cGMP-binding, cGMP-specific phosphodiesterase, a member of the cyclic nucleotide phosphodiesterase family. This phosphodiesterase specifically hydrolyzes cGMP to 5’-GMP. It is involved in the regulation of intracellular concentrations of cyclic nucleotides and is important for smooth muscle relaxation in the cardiovascular system. Alternative splicing of this gene results in three transcript variants encoding distinct isoforms.

Source: NCBI Gene 8654 — RefSeq curated summary.

At a glance

• GWAS associations: 20
• Clinical variants (ClinVar): 134 total
• GTEx eGene: eQTL in 20 tissues, sQTL in 11 (q < 0.05)
• Drug target: yes — 9 curated mechanism-of-action drugs; 30 molecules with ChEMBL bioactivity (top 1% of genes corpus-wide)
• Approved drugs (ChEMBL mechanism of action): 5 — Avanafil, Ibudilast, Sildenafil Citrate, +2 more
• Constraint (gnomAD): pLI 0.01 (LoF-tolerant), LOEUF 0.70 (unconstrained)
• MANE Select transcript: NM_001083
• Notable: 134 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8784
Approved symbol	PDE5A
Name	phosphodiesterase 5A
Location	4q26
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000138735
Ensembl biotype	protein_coding
OMIM	603310
Entrez	8654

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 14 protein_coding, 4 protein_coding_CDS_not_defined, 3 retained_intron

MANE Select: ENST00000354960

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 3: 7, TSL 4: 2, TSL 5: 1

ENST00000354960, ENST00000264805, ENST00000394439, ENST00000420633, ENST00000502912, ENST00000503412, ENST00000508914, ENST00000509612, ENST00000512450, ENST00000512494, ENST00000512739, ENST00000513594, ENST00000925607, ENST00000925608, ENST00001107782, ENST00001107783, ENST00001107784, ENST00001107785, ENST00001114621, ENST00001114622, ENST00001140670

RefSeq mRNA: 3 — MANE Select: NM_001083 NM_001083, NM_033430, NM_033437

CCDS: CCDS34055, CCDS3713

Canonical transcript exons

ENST00000354960 — 21 exons

Exon	Start	End
ENSE00000935544	119596523	119596612
ENSE00000970323	119567073	119567144
ENSE00000970324	119565321	119565410
ENSE00000970325	119562833	119562970
ENSE00000970328	119552550	119552637
ENSE00001016840	119507604	119507704
ENSE00001016841	119502581	119502655
ENSE00001016845	119501170	119501253
ENSE00001016847	119505855	119505932
ENSE00001851914	119628520	119628804
ENSE00001890486	119494403	119498738
ENSE00003460007	119520935	119521060
ENSE00003462098	119525549	119525695
ENSE00003536164	119504536	119504599
ENSE00003537282	119542459	119542634
ENSE00003557390	119560296	119560363
ENSE00003566974	119538960	119539019
ENSE00003574404	119519045	119519139
ENSE00003630080	119511047	119511134
ENSE00003641439	119553638	119553746
ENSE00003651847	119606709	119607297

Expression profiles

Bgee: expression breadth ubiquitous, 236 present calls, max score 97.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.6332 / max 264.5648, expressed in 1112 samples.

Highest expression (Bgee): calcaneal tendon, descending thoracic aorta, colonic epithelium, thoracic aorta, cauda epididymis.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PDE5A is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 20 tissues and its splicing (sQTL) in 11 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 31 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	sqtl	1.6e-16	-0.74	4:119517019:G:T
Artery Tibial	sqtl	2.5e-10	+0.40	4:119404277:C:T
Artery Aorta	eqtl	2.6e-09	+0.17	4:119980181:A:G
Colon Sigmoid	eqtl	5.2e-08	-0.17	4:119666626:C:T
Artery Aorta	sqtl	2.0e-07	-0.46	4:119628303:G:GCAAGTACATTTTTGTATTTGAAC
Muscle Skeletal	eqtl	5.7e-07	-0.12	4:119678506:T:C
Nerve Tibial	sqtl	1.3e-05	+0.36	4:119578501:T:C
Heart Atrial Appendage	eqtl	1.8e-05	+0.15	4:119843215:T:C
Thyroid	eqtl	2.5e-05	-0.15	4:119591880:A:G
Skin Sun Exposed Lower leg	eqtl	4.7e-05	-0.11	4:119817862:A:G
Esophagus Gastroesophageal Junction	sqtl	5.0e-05	-0.45	4:119484107:G:A
Cells EBV-transformed lymphocytes	eqtl	8.2e-05	-0.34	4:119247433:T:C
Skin Not Sun Exposed Suprapubic	eqtl	1.9e-04	+0.10	4:119735501:G:C
Nerve Tibial	eqtl	3.0e-04	-0.08	4:119707472:T:C
Artery Tibial	eqtl	4.3e-04	-0.23	4:119474818:A:G
Adipose Subcutaneous	sqtl	7.5e-04	+0.30	4:119584998:G:A
Spleen	eqtl	7.5e-04	-0.29	4:119140180:T:C
Adipose Subcutaneous	eqtl	1.3e-03	-0.09	4:119868619:A:G
Artery Coronary	sqtl	1.7e-03	-0.53	4:119666060:G:A
Adrenal Gland	eqtl	1.8e-03	-0.17	4:119735501:G:C

FANTOM5 promoters

showing 10 of 14 alternative TSS:

Promoter ID	TPM avg	Samples expressed
53773	1.8396	556
53776	1.3340	608
53763	1.1194	438
53771	0.8868	329
53769	0.6007	237
53766	0.4675	205
53764	0.3289	164
53767	0.3058	150
53770	0.3050	156
53774	0.2180	109

Top tissues by expression

showing 100 of 282 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	97.81	gold quality
descending thoracic aorta	UBERON:0002345	96.63	gold quality
colonic epithelium	UBERON:0000397	96.21	gold quality
thoracic aorta	UBERON:0001515	96.10	gold quality
cauda epididymis	UBERON:0004360	96.09	gold quality
ascending aorta	UBERON:0001496	96.05	gold quality
right coronary artery	UBERON:0001625	95.98	gold quality
aorta	UBERON:0000947	95.90	gold quality
popliteal artery	UBERON:0002250	95.79	gold quality
tibial artery	UBERON:0007610	95.78	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.49	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.45	gold quality
lower esophagus	UBERON:0013473	95.44	gold quality
mucosa of stomach	UBERON:0001199	95.39	gold quality
artery	UBERON:0001637	95.36	gold quality
caput epididymis	UBERON:0004358	94.83	gold quality
rectum	UBERON:0001052	94.33	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.31	gold quality
left coronary artery	UBERON:0001626	93.51	gold quality
corpus epididymis	UBERON:0004359	93.15	gold quality
visceral pleura	UBERON:0002401	92.59	gold quality
right uterine tube	UBERON:0001302	92.52	gold quality
coronary artery	UBERON:0001621	92.51	gold quality
urethra	UBERON:0000057	92.32	gold quality
sigmoid colon	UBERON:0001159	91.90	gold quality
seminal vesicle	UBERON:0000998	91.59	gold quality
endocervix	UBERON:0000458	91.40	gold quality
superficial temporal artery	UBERON:0001614	91.40	gold quality
sural nerve	UBERON:0015488	91.40	gold quality
right lung	UBERON:0002167	91.23	gold quality
tibial nerve	UBERON:0001323	90.78	gold quality
ectocervix	UBERON:0012249	90.49	gold quality
prostate gland	UBERON:0002367	90.20	gold quality
adrenal tissue	UBERON:0018303	90.05	gold quality
stromal cell of endometrium	CL:0002255	89.86	gold quality
vagina	UBERON:0000996	89.50	gold quality
large intestine	UBERON:0000059	89.42	gold quality
colon	UBERON:0001155	89.40	gold quality
left lobe of thyroid gland	UBERON:0001120	89.15	gold quality
body of pancreas	UBERON:0001150	89.11	gold quality
right lobe of thyroid gland	UBERON:0001119	89.10	gold quality
intestine	UBERON:0000160	89.01	gold quality
transverse colon	UBERON:0001157	88.88	gold quality
thyroid gland	UBERON:0002046	88.74	gold quality
esophagus	UBERON:0001043	88.69	gold quality
body of uterus	UBERON:0009853	88.65	gold quality
left uterine tube	UBERON:0001303	88.55	gold quality
gall bladder	UBERON:0002110	88.47	gold quality
subcutaneous adipose tissue	UBERON:0002190	88.43	gold quality
upper lobe of left lung	UBERON:0008952	88.10	gold quality
parietal pleura	UBERON:0002400	88.02	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.87	gold quality
pleura	UBERON:0000977	87.77	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.60	gold quality
right ovary	UBERON:0002118	87.58	gold quality
upper lobe of lung	UBERON:0008948	87.57	gold quality
monocyte	CL:0000576	87.51	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.23	gold quality
small intestine	UBERON:0002108	87.17	gold quality
tendon	UBERON:0000043	87.10	gold quality
left ovary	UBERON:0002119	86.99	gold quality
fundus of stomach	UBERON:0001160	86.62	gold quality
urinary bladder	UBERON:0001255	86.59	gold quality
cerebellar hemisphere	UBERON:0002245	86.57	gold quality
mononuclear cell	CL:0000842	86.53	gold quality
pancreas	UBERON:0001264	86.44	gold quality
cerebellar cortex	UBERON:0002129	86.38	gold quality
saphenous vein	UBERON:0007318	86.01	gold quality
leukocyte	CL:0000738	85.99	gold quality
stomach	UBERON:0000945	85.88	gold quality
adenohypophysis	UBERON:0002196	85.82	gold quality
omental fat pad	UBERON:0010414	85.81	gold quality
peritoneum	UBERON:0002358	85.76	gold quality
minor salivary gland	UBERON:0001830	85.38	gold quality
skin of leg	UBERON:0001511	85.37	gold quality
metanephros cortex	UBERON:0010533	85.10	gold quality
adipose tissue of abdominal region	UBERON:0007808	85.06	gold quality
body of stomach	UBERON:0001161	84.75	gold quality
skin of abdomen	UBERON:0001416	84.59	gold quality
islet of Langerhans	UBERON:0000006	84.47	gold quality
mucosa of transverse colon	UBERON:0004991	84.40	gold quality
ovary	UBERON:0000992	84.38	gold quality
smooth muscle tissue	UBERON:0001135	84.06	gold quality
adipose tissue	UBERON:0001013	83.93	gold quality
connective tissue	UBERON:0002384	83.68	gold quality
skin of hip	UBERON:0001554	83.63	gold quality
cerebellum	UBERON:0002037	83.53	gold quality
lung	UBERON:0002048	83.53	gold quality
saliva-secreting gland	UBERON:0001044	83.40	gold quality
pituitary gland	UBERON:0000007	83.34	gold quality
right atrium auricular region	UBERON:0006631	83.29	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.24	gold quality
gastrocnemius	UBERON:0001388	83.06	gold quality
muscle of leg	UBERON:0001383	82.98	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	82.97	gold quality
adrenal gland	UBERON:0002369	82.92	gold quality
zone of skin	UBERON:0000014	82.80	gold quality
female reproductive system	UBERON:0000474	82.79	gold quality
left adrenal gland cortex	UBERON:0035825	82.56	gold quality
left adrenal gland	UBERON:0001234	82.49	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.13

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Prostate	tissue	56.1	medium
Seminal vesicle	tissue	46.9	low
Epididymis	tissue	39.2	medium
Esophagus	tissue	38.8	medium
Choroid plexus	tissue	36.5
Cervix	tissue	30.8	medium
Rectum	tissue	24.4	medium
Fallopian tube	tissue	21.6	medium
Lung	tissue	21.0	medium
Nucleus accumbens	tissue	19.1
Colon	tissue	19.0	medium
Small intestine	tissue	17.9	medium
Superior colliculi	tissue	16.9
Postcentral gyrus	tissue	16.4
Thyroid gland	tissue	15.9	medium
Vagina	tissue	14.8	not detected
Duodenum	tissue	14.7	medium
Urinary bladder	tissue	13.7	medium
Endometrium 1	tissue	13.7	medium
Adipose tissue	tissue	13.3	medium
Locus coeruleus	tissue	12.6
Placenta	tissue	12.5	medium
Heart muscle	tissue	12.1	medium
Pancreas	tissue	11.9	medium
Spinal cord	tissue	11.8
Hippocampus	tissue	11.7	medium
Olfactory bulb	tissue	11.5
Substantia nigra	tissue	10.9
Adrenal gland	tissue	10.8	medium
Smooth muscle	tissue	10.6	medium
Appendix	tissue	10.5	medium
Cerebellum	tissue	9.9	medium
Retina	tissue	9.8
Gallbladder	tissue	9.8	medium
Salivary gland	tissue	9.3	medium
Testis	tissue	9.2	medium
Stomach 1	tissue	8.6	medium
Breast	tissue	8.0	medium
Parathyroid gland	tissue	7.8	medium
Cerebral cortex	tissue	7.2	medium
Motor cortex	tissue	7.2
Thalamus	tissue	6.9
Skeletal muscle	tissue	6.7	medium
Hippocampal formation	tissue	6.7
Ovary	tissue	6.5	medium
Entorhinal cortex	tissue	6.2
Lymph node	tissue	6.1	low
Midbrain	tissue	6.0
Medulla oblongata	tissue	5.8
Retrosplenial and cingulate cortex	tissue	5.8
Spleen	tissue	5.6	medium
Kidney	tissue	5.6	medium
Retrosplenial cortex	tissue	5.6
Prefrontal cortex	tissue	5.5
Pons	tissue	5.5
Tongue	tissue	5.3
Insular cortex	tissue	5.2
Temporal cortex	tissue	5.1
Hypothalamus	tissue	5.0
Somatosensory cortex	tissue	4.9

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Blood vessel (54.9), Periaquaductal grey, anterior (28.6), Vermis (21.4), Cerebellar cortex (21.2), Nuclei of the trapezoid body (20.9).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): POU3F2

miRNA regulators (miRDB)

Targeting PDE5A by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 247 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4500	99.99	72.72	2367

Functional genomics

gnomAD constraint: pLI 0.00649, LOEUF 0.704, missense Z 1.55 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000354960 — one region, missense o/e 0.82.

Literature-anchored findings (GeneRIF, showing 40)

• Human PDE5A gene encodes three PDE5 isoforms from two alternate promoters. (PMID:11896473)
• cGMP-directed regulation of PDE5 phosphorylation and the resulting increase in cGMP binding affinity occur largely within the R domain (PMID:12359732)
• CGMP-dependent protein kinase I causes NO-induced PDE5 phosphorylation. However, cGMP can directly activate PDE5 without phosphorylation in platelet cytosol, most likely by binding to GAF domains. (PMID:12604588)
• GAFa domain of PDE5A adopts a structure similar to the GAFb domain of PDE2A, and provides the sole site for cGMP binding in PDE5A (PMID:12650945)
• three-dimensional structures of the catalytic domain (residues 537-860) of human PDE5 complexed with the three drug molecules sildenafil, tadalafil (Cialis) and vardenafil (Levitra) (PMID:12955149)
• Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor 3-isobutyl-1-methylxanthine (PMID:14668322)
• demonstrated, for the first time, that androgens positively regulate phosphodiesterase 5 (PMID:14764637)
• no correlations of a novel polymorphism of the PDE5A promoter gene with the intermediate phenotype essential hypertension/erectile dysfunction (PMID:15175637)
• Phosphorylation of PDE5 seems to act as memory switch for activation leading to long-term desensitization of the signaling pathway. (PMID:15240816)
• PDE5 gene expression and activity are androgen-dependent in vas deferens. (PMID:15640438)
• Phosphodiesterase Type 5 is the main factor regulating cyclic guanosine monophosphate hydrolysis and downstream signaling in human PASMCs. (PMID:15817798)
• Results suggest that glutamine(817) is a positive determinant for phosphodiesterase 5 affinity for cyclic GMP and several inhibitors. (PMID:16407275)
• Subdomains are structurally and functionally interdependent and act in concert in regulating human PDE5. (PMID:16690614)
• Virtually all tissues and cell types express PDE5, with heart and cardiomyocytes being contentious; PDE5A1 and PDE5A2 are ubiquitous, but PDE5A3 is specific to smooth muscle, as described in this review. (PMID:17017938)
• PDE5 may be a possible therapeutic target in bladder dysfunction for ameliorating irritative lower urinary tract symptoms. (PMID:17138653)
• The PDE-5A was expressed in both pre-adipocytes and adipocytes. PDE-5A mRNA and protein levels decreased as pre-adipocytes differentiated. (PMID:17906676)
• GAF domains of PDE5A can act as sensors and intracellular sinks for cyclic GMP, but not cyclic AMP. (PMID:18293931)
• analysis of functional chimeras of the phosphodiesterase 5 and 10 tandem GAF domains (PMID:18635550)
• may define a molecular mechanism by which PDE5 inhibition can differentially impact selected cellular functions of platelets, and perhaps of other cell types (PMID:18757735)
• Increased myocardial PDE5 expression in patients with advanced cardiomyopathy may contribute to the development of heart failure and represents an important therapeutic target. (PMID:19139381)
• The rAd5-shRNA-PDE5A3 can obviously increase the cGMP level in the smooth muscle cells of human corpus cavernosum, and enhance the inhibition of the PDE5 gene. (PMID:19852267)
• PDE5-inhibition blocks TRPC6 channel activation and associated Cn/NFAT activation signaling by PKG-dependent channel phosphorylation (PMID:19961855)
• Data show that SS increased intracellular cGMP levels and activated protein kinase G, and selectively inhibited PDE5 in breast tumor cells. (PMID:19996273)
• The distribution of PDE-5 and NOD II may indicate a physiologic role in the regulatory function of human vagina. (PMID:20177899)
• Data show that the identified compound will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. (PMID:20196613)
• Myocardial oxidative stress increases PDE5 expression in the failing heart (PMID:20308615)
• High PDE5A1 expression is associated with malignant melanoma. (PMID:20332439)
• Suggest that PDE5A is associated with increased disease susceptibility, pathological progression, and development of proteinuria in childhood IgA nephropathy. (PMID:20563733)
• Conformation changes, N-terminal involvement, and cGMP signal relay in the phosphodiesterase-5 GAF domain. (PMID:20861010)
• Distinct allostery induced in the cyclic GMP-binding, cyclic GMP-specific phosphodiesterase (PDE5) by cyclic GMP, sildenafil, and metal ions. (PMID:21193396)
• In melanoma cells, oncogenic (V600E) BRAF signaling downregulates PDE5A through the transcription factor BRN2, leading to increased cGMP and Ca2+ and the induction of invasion through increased cell contractility. (PMID:21215707)
• the spatial localization of PDE5A at the level of caveolin-rich lipid rafts allows for a feedback loop between endothelial PDE5A and nitric oxide synthase (NOS3) (PMID:21421555)
• Solved is the crystal structure of the structurally uncharacterized PDE5A GAF-B domain. (PMID:21425347)
• PDE5 inhibition by sulindac sulfide selectively induces apoptosis and attenuates oncogenic Wnt/beta-catenin-mediated transcription in human breast tumor cells (PMID:21505183)
• These studies suggest a novel role for PDE5 in erythrocytes. (PMID:21525805)
• found in smooth muscle wall of blood vessels transversing the clitoral supepithelial and stromal space (PMID:21697861)
• PDE9 is widely distributed in the urothelial epithelium of the human lower urinary tract and its potential roles may be different from those of PDE5. (PMID:21736695)
• Treatment of L-1236 with PDE5A-inhibitor sildenafil or with siRNA directed against PDE5A and concomitant stimulation with cyclic guanosine monophosphate (cGMP) resulted in enhanced apoptosis, indicating PDE5A as an oncogene. (PMID:21987443)
• PDE5 is highly expressed and increases ( approximately 130%) during growth whereas ABCC5 exhibited low to moderate expression, with a moderate increase ( approximately 40%) during growth (PMID:22843873)
• it is concluded that assessment of PDE5 and PDE9 expression may be useful in the differential diagnosis of benign and malignant breast disease and successful treatment of breast cancer (PMID:22960860)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	pde5ab	ENSDARG00000051915
mus_musculus	Pde5a	ENSMUSG00000053965
rattus_norvegicus	Pde5a	ENSRNOG00000014443
drosophila_melanogaster	Pde11	FBGN0085370
drosophila_melanogaster	Pde8	FBGN0266377
caenorhabditis_elegans		WBGENE00008443
caenorhabditis_elegans	pde-6	WBGENE00022389

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), PDE3B (ENSG00000152270), PDE1C (ENSG00000154678), PDE9A (ENSG00000160191), PDE7B (ENSG00000171408), PDE3A (ENSG00000172572), PDE4B (ENSG00000184588), PDE2A (ENSG00000186642), PDE7A (ENSG00000205268)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2651499) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 4 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal liver morphology	1
small liver	1
decreased body length	1
abnormal caudal vertebrae morphology	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pan troglodytes	H2QL32	99.5%	Diamond
Drosophila erecta	B3P3K2	98.3%	Diamond
Drosophila simulans	B4QZU1	98.3%	Diamond
Drosophila yakuba	B4PSS5	96.8%	Diamond
Drosophila mojavensis	B4K9L4	96.7%	Diamond
Drosophila virilis	B4LVU6	96.7%	Diamond
Canis lupus familiaris	Q28263	96.3%	Diamond
Drosophila grimshawi	B4JXX2	95.6%	Diamond
Bos taurus	Q28156	95.6%	Diamond
Drosophila willistoni	B4NAL6	94.8%	Diamond
Drosophila pseudoobscura pseudoobscura	Q298P4	94.8%	Diamond
Drosophila ananassae	B3LVW5	93.1%	Diamond
Drosophila sechellia	B4HEM4	91.0%	Diamond
Drosophila persimilis	B4G4E5	86.3%	Diamond
Gallus gallus	P52731	84.0%	Diamond
Takifugu rubripes	Q1KKS3	81.6%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
LINC01061	ncRNA	401149
LINC01365	ncRNA	101927007
LINC02502	ncRNA	100996694

Protein

Protein identifiers

cGMP-specific 3’,5’-cyclic phosphodiesterase — O76074 (reviewed: O76074)

Alternative names: cGMP-binding cGMP-specific phosphodiesterase

All UniProt accessions (4): C9JGT3, G5E9C5, H0YA14, O76074

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5’-GMP. Specifically regulates nitric-oxide-generated cGMP.

Tissue specificity. Expressed in aortic smooth muscle cells, heart, placenta, skeletal muscle and pancreas and, to a much lesser extent, in brain, liver and lung.

Post-translational modifications. Phosphorylation is regulated by binding of cGMP to the two allosteric sites. Phosphorylation by PRKG1 leads to its activation.

Activity regulation. Sildenafil (Viagra) is a highly selective and potent inhibitor of PDE5A and is effective in the treatment of penile erectile dysfunction. Also inhibited by zaprinast.

Cofactor. Binds 1 Zn(2+) ion per subunit. Binds 2 divalent metal cations per subunit: site 1 preferentially binds zinc, while site 2 has a preference for magnesium. Tightly binds zinc. Binds 1 Mg(2+) ions per subunit. Binds 2 divalent metal cations per subunit: site 1 preferentially binds zinc, while site 2 has a preference for magnesium. Binds magnesium less tightly than zinc.

Domain organisation. Composed of a C-terminal catalytic domain containing two putative divalent metal sites and an N-terminal regulatory domain which contains two homologous allosteric cGMP-binding regions, A and B.

Pathway. Purine metabolism; 3’,5’-cyclic GMP degradation; GMP from 3’,5’-cyclic GMP: step 1/1.

Similarity. Belongs to the cyclic nucleotide phosphodiesterase family.

Isoforms (2)

UniProt ID	Names	Canonical?
O76074-1	PDE5A1	yes
O76074-2	PDE5A2

RefSeq proteins (3): NP_001074, NP_236914, NP_246273 (=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 3.1.4.35 — 3’,5’-cyclic-GMP phosphodiesterase (BRENDA: 27 organisms, 45 substrates, 302 inhibitors, 50 Km, 11 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
CGMP	0.0002–1.6	25
3’,5’-CGMP	0.0003–1	16
3’,5’-CAMP	0.001–0.82	5
2’-O-ANTHRANILOYL-CGMP	0.0247–0.0651	2
2’-O-ANTHRANILOYL CGMP	0.012	1

Catalyzed reactions (Rhea)

• 3’,5’-cyclic GMP + H2O = GMP + H(+) (RHEA:16957)

UniProt features (98 total): helix 39, strand 21, turn 11, binding site 6, sequence conflict 5, domain 3, mutagenesis site 3, sequence variant 2, region of interest 2, compositionally biased region 2, chain 1, modified residue 1, splice variant 1, active site 1

Structure

Experimental structures (PDB)

showing 30 of 50 structures by resolution:

PDB	Title	Method	Resolution (Å)
1TBF	Catalytic Domain Of Human Phosphodiesterase 5A in Complex with Sildenafil	X-RAY DIFFRACTION	1.3
1XOZ	Catalytic Domain Of Human Phosphodiesterase 5A In Complex With Tadalafil	X-RAY DIFFRACTION	1.37
5JO3	PDE5A for NaV1.7	X-RAY DIFFRACTION	1.49
2CHM	Crystal structure of N2 substituted pyrazolo pyrimidinones - a flipped binding mode in …	X-RAY DIFFRACTION	1.6
1XP0	Catalytic Domain Of Human Phosphodiesterase 5A In Complex With Vardenafil	X-RAY DIFFRACTION	1.79
3HC8	Investigation of Aminopyridiopyrazinones as PDE5 Inhibitors: Evaluation of Modifications …	X-RAY DIFFRACTION	1.79
2H44	Crystal structure of PDE5A1 in complex with icarisid II	X-RAY DIFFRACTION	1.8
3HDZ	Identification, Synthesis, and SAR of Amino Substituted Pyrido[3,2b]pryaziones as Potent …	X-RAY DIFFRACTION	1.8
8W4S	Crystal structure of PDE5A in complex with CVT-313	X-RAY DIFFRACTION	1.85
2H40	Crystal structure of the catalytic domain of unliganded PDE5	X-RAY DIFFRACTION	1.85
3TGG	A novel series of potent and selective PDE5 inhibitor2	X-RAY DIFFRACTION	1.91
6L6E	Human PDE5 catalytic core in complex with avanafil	X-RAY DIFFRACTION	1.92
3SIE	Crystal structure of the PDE5A1 catalytic domain in complex with novel inhibitors	X-RAY DIFFRACTION	1.93
3TGE	A novel series of potent and selective PDE5 inhibitor1	X-RAY DIFFRACTION	1.96
1T9S	Catalytic Domain Of Human Phosphodiesterase 5A in Complex with GMP	X-RAY DIFFRACTION	2
3BJC	Crystal structure of the PDE5A catalytic domain in complex with a novel inhibitor	X-RAY DIFFRACTION	2
4MD6	Crystal structure of PDE5 in complex with inhibitor 5R	X-RAY DIFFRACTION	2
1RKP	Crystal structure of PDE5A1-IBMX	X-RAY DIFFRACTION	2.05
3B2R	Crystal Structure of PDE5A1 catalytic domain in complex with Vardenafil	X-RAY DIFFRACTION	2.07
4I9Z	Crystal structure of the PDE5A1 catalytic domain in complex with novel inhibitors	X-RAY DIFFRACTION	2.08
1T9R	Catalytic Domain Of Human Phosphodiesterase 5A	X-RAY DIFFRACTION	2.1
4OEX	Crystal structure of the PDE5A1 catalytic domain in complex with novel inhibitors	X-RAY DIFFRACTION	2.14
6IWI	Crystal structure of PDE5A in complex with a novel inhibitor	X-RAY DIFFRACTION	2.15
4IA0	Crystal structure of the PDE5A1 catalytic domain in complex with novel inhibitors	X-RAY DIFFRACTION	2.17
8W4T	Crystal structure of PDE5A in complex with a novel inhibitor	X-RAY DIFFRACTION	2.2
7FAQ	Crystal structure of PDE5A in complex with inhibitor L1	X-RAY DIFFRACTION	2.2
4G2W	Crystal structure of PDE5A in complex with its inhibitor	X-RAY DIFFRACTION	2.28
1UDT	Crystal structure of Human Phosphodiesterase 5 complexed with Sildenafil(Viagra)	X-RAY DIFFRACTION	2.3
2H42	Crystal structure of PDE5 in complex with sildenafil	X-RAY DIFFRACTION	2.3
6VBI	crystal structure of PDE5 in complex with a non-competitive inhibitor	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O76074-F1	82.32	0.46

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Metabolic proteins, Predicted intracellular proteins, FDA approved drug targets, Small molecule drugs

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; basal body

Antibody reliability (HPA): IH approved · IF approved

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)

Position	Role
613	proton donor

Ligand- & substrate-binding residues (6)

Position	Role
653	Zn(2+)
654	Mg(2+)
654	Zn(2+)
764	Zn(2+)
817	3’,5’-cyclic GMP
617	Zn(2+)

Post-translational modifications (1)

Type	Positions
Phosphoserine	102

Mutagenesis-validated functional residues (3)

Position	Phenotype
767	changes substrate selectivity from cgmp-specific to dual camp and cgmp binding and hydrolysis; when associated with y-775 and y-853.
775	changes substrate selectivity from cgmp-specific to dual camp and cgmp binding and hydrolysis; when associated with n-767 and y-853.
853	changes substrate selectivity from cgmp-specific to dual camp and cgmp binding and hydrolysis; when associated with n-767 and y-775.

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 12; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

12 pathways:

ID	Pathway	Evidence
R-HSA-9013422	RHOBTB1 GTPase cycle	curated
R-HSA-445355	Smooth Muscle Contraction	curated
R-HSA-418457	cGMP effects	curated
R-HSA-109582	Hemostasis	—
R-HSA-397014	Muscle contraction	—
R-HSA-392154	Nitric oxide stimulates guanylate cyclase	—
R-HSA-418346	Platelet homeostasis	—
R-HSA-9012999	RHO GTPase cycle	—
R-HSA-9706574	RHOBTB GTPase Cycle	—
R-HSA-162582	Signal Transduction	—
R-HSA-194315	Signaling by Rho GTPases	—
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3	—

MSigDB gene sets: 199 (showing top): GGTGTGT_MIR329, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, MODULE_65, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CYCLIC_NUCLEOTIDE_METABOLIC_PROCESS, CHANDRAN_METASTASIS_DN, GOBP_CYCLIC_NUCLEOTIDE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GTGCCTT_MIR506, BROWNE_HCMV_INFECTION_14HR_DN, GOBP_ORGANOPHOSPHATE_CATABOLIC_PROCESS, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN

GO Biological Process (3): signal transduction (GO:0007165), cGMP catabolic process (GO:0046069), negative regulation of cAMP/PKA signal transduction (GO:0141162)

GO Molecular Function (10): 3’,5’-cyclic-nucleotide phosphodiesterase activity (GO:0004114), 3’,5’-cyclic-AMP phosphodiesterase activity (GO:0004115), cGMP binding (GO:0030553), metal ion binding (GO:0046872), 3’,5’-cyclic-GMP phosphodiesterase activity (GO:0047555), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), phosphoric diester hydrolase activity (GO:0008081), hydrolase activity (GO:0016787)

GO Cellular Component (1): cytosol (GO:0005829)

Reactome top-level categories

9 top-level categories:

Category	Pathways
Nitric oxide stimulates guanylate cyclase	1
Muscle contraction	1
RHOBTB GTPase Cycle	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Platelet homeostasis	1
Hemostasis	1
Signaling by Rho GTPases	1
RHO GTPase cycle	1
Signal Transduction	1

GO top-level categories

25 GO namespaces:

Category	Terms
3’,5’-cyclic-nucleotide phosphodiesterase activity	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
purine ribonucleotide catabolic process	1
cyclic nucleotide catabolic process	1
cGMP metabolic process	1
cAMP/PKA signal transduction	1
regulation of cAMP/PKA signal transduction	1
negative regulation of intracellular signal transduction	1
cyclic-nucleotide phosphodiesterase activity	1
cyclic nucleotide binding	1
guanyl ribonucleotide binding	1
anion binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
phosphoric ester hydrolase activity	1
catalytic activity	1
cytoplasm	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 1 of 14 annotations. The rest are phylogenetic / computational / electronic (IEA).

1 experimentally-supported GO terms:

GO term	NS	Evidence
3’,5’-cyclic-GMP phosphodiesterase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,260 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDE5A	ALDH7A1	P49419	945
PDE5A	PRKG1	P14619	727
PDE5A	NOS3	P29474	653
PDE5A	EDN1	P05305	615
PDE5A	NOS1	P29475	615
PDE5A	GUCY1B1	Q02153	603
PDE5A	NPPA	P01160	583
PDE5A	SEPTIN8	Q92599	570
PDE5A	SEPTIN3	Q9UH03	567
PDE5A	ACE	P12821	550
PDE5A	EDNRA	P25101	548
PDE5A	PTGIR	P43119	547
PDE5A	VASP	P50552	530
PDE5A	PRKG2	Q13237	516
PDE5A	AGT	P01019	507

IntAct

Human interaction partners of PDE5A in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

12 partners by confidence:

Partner	Interaction type	MIscore	Records
AIPL1	association	0.640	2
SPG21	physical association	0.560	3
PRKG1	association	0.500	4
H2BC9	physical association	0.400	1
ITPR1	association	0.350	1
BLM	physical association	0.000	1
CEP43	physical association	0.000	1
FKBP15	physical association	0.000	1
MIOS	physical association	0.000	1
PATZ1	physical association	0.000	1
SUPT5H	physical association	0.000	1
WDR24	physical association	0.000	1

BioGRID (25 interactions; top human partners by supporting records): RHOBTB1 (Affinity Capture-Western; 5 records), AIPL1 (Affinity Capture-MS; 2 records), BLM (Affinity Capture-MS), DDX39A (Affinity Capture-RNA), DYRK1A (Affinity Capture-MS), FGFR1OP (Affinity Capture-MS), FKBP15 (Affinity Capture-MS), HIST1H2BH (Cross-Linking-MS (XL-MS)), MIOS (Affinity Capture-MS), MSH5 (Affinity Capture-MS), NUDT21 (Affinity Capture-RNA), PARP1 (Proximity Label-MS), PARP12 (Proximity Label-MS), PARP16 (Proximity Label-MS), PARP4 (Proximity Label-MS)

SIGNOR signaling

5 signaling interactions:

A	Effect	B	Mechanism
icariin	down-regulates	PDE5A	“chemical inhibition”
tadalafil	“down-regulates activity”	PDE5A	“chemical inhibition”
RHOBTB1	“down-regulates quantity by destabilization”	PDE5A	binding
“Cullin 3-RBX1-Skp1”	“down-regulates quantity by destabilization”	PDE5A	polyubiquitination
sildenafil	“down-regulates activity”	PDE5A	“chemical inhibition”

Protein complexes (CORUM) (4)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

4 complexes by size:

Complex	Subunits	Members
★ ITPR1-MRVI1-PDE5A-PRKG1 complex	4	IRAG1, ITPR1, PDE5A, PRKG1
★ AIPL1-PDE5A complex	2	PDE5A, AIPL1
★ MSH5-PDE5A complex	2	MSH5, PDE5A
★ PDE5A homodimer	1	PDE5A

Disease & clinical

Genetic variants

Variant evidence for PDE5A: 134 ClinVar records (0 pathogenic / likely pathogenic); 20 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	87
Likely benign	10
Benign	6

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 25 predictions of 1,869):

Position(s)	Effect	Δscore	Sites
4:119502579–119502580	donor_loss	1.0000	5
4:119502656–119502657	acceptor_loss	1.0000	4
4:119505853–119505854	donor_loss	1.0000	5
4:119507607	donor_gain	1.0000
4:119507705	acceptor_loss	1.0000
4:119507707	acceptor_gain	1.0000
4:119511141	acceptor_gain	1.0000
4:119511146	acceptor_gain	1.0000
4:119511149	acceptor_gain	1.0000
4:119519043–119519044	donor_loss	1.0000	5

AlphaMissense

2,474 missense substitutions predicted likely pathogenic (of 5,871 scored), across 558 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M805	9	0.948	0.998
M760	9	0.883	0.995
D654	8	0.998	1.000
D764	8	0.998	1.000
D656	8	0.997	0.999
H657	8	0.997	0.999
H685	8	0.997	0.999
D256	8	0.996	0.999
H653	8	0.996	0.999
H684	8	0.996	0.999
H613	8	0.995	0.999
H617	8	0.995	0.999
F309	8	0.987	0.999
F188	8	0.986	0.999
D724	8	0.986	0.998
F205	8	0.985	0.999
F295	8	0.985	0.999
N849	8	0.985	0.997
H529	8	0.982	0.998
F251	8	0.981	1.000

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Thyroid Carcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Chromophobe (TCGA)	unfavorable	0.000176
Breast Invasive Carcinoma (validation)	unfavorable	0.000393
Kidney Renal Clear Cell Carcinoma (validation)	favorable	0.00062

Disease associations

OMIM: gene MIM:603310 | disease phenotypes:

GWAS associations

20 associations:

Study	Trait	p-value
GCST007094_162	Diastolic blood pressure	9e-19
GCST010002_139	Refractive error	5e-18
GCST004280_86	Diastolic blood pressure	3e-15
GCST90020029_498	Waist circumference adjusted for body mass index	2e-14
GCST90020024_130	A body shape index	2e-13
GCST004607_175	Plateletcrit	6e-10
GCST007487_3	Waist-to-hip ratio adjusted for BMI (additive genetic model)	1e-9
GCST004603_200	Platelet count	3e-9
GCST007500_8	Waist-to-hip ratio adjusted for BMI (additive genetic model)	5e-9
GCST007502_29	Waist-to-hip ratio adjusted for BMI (additive genetic model)	5e-9
GCST008363_108	Offspring birth weight	9e-9
GCST004787_7	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	1e-8
GCST90020029_497	Waist circumference adjusted for body mass index	1e-8
GCST007099_127	Systolic blood pressure	2e-8
GCST010479_20	Coronary artery disease	2e-8
GCST90020024_131	A body shape index	2e-8
GCST90020025_742	Waist-to-hip ratio adjusted for BMI	2e-8
GCST90020027_1612	Waist-hip index	2e-8
GCST007483_49	Waist-to-hip ratio adjusted for BMI (additive genetic model)	3e-8
GCST008163_172	Height	1e-6

EFO canonical traits (from GWAS)

8 canonical traits:

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0004309	platelet count
EFO:0007985	platelet crit
EFO:0006335	systolic blood pressure
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (8): CHEMBL1827 (SINGLE PROTEIN), CHEMBL2095220 (SELECTIVITY GROUP), CHEMBL2097161 (PROTEIN FAMILY), CHEMBL2111340 (SELECTIVITY GROUP), CHEMBL2111400 (SELECTIVITY GROUP), CHEMBL2111470 (SELECTIVITY GROUP), CHEMBL2363066 (PROTEIN FAMILY), CHEMBL4523626 (CHIMERIC PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the PDE5A protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

9 curated-mechanism drugs:

Drug	Modality	Max phase
AVANAFIL	Small molecule	4
IBUDILAST	Small molecule	4
SILDENAFIL CITRATE	Small molecule	4
TADALAFIL	Small molecule	4
VARDENAFIL HYDROCHLORIDE	Small molecule	4
UDENAFIL	Small molecule	3
GISADENAFIL	Small molecule	2
PF-00489791	Small molecule	2
PF-03049423	Small molecule	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 418,827 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

30 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1963681	AVANAFIL	4	4,983
CHEMBL19449	IBUDILAST	4	7,547
CHEMBL192	SILDENAFIL	4	42,240
CHEMBL1737	SILDENAFIL CITRATE	4	16,469
CHEMBL779	TADALAFIL	4	23,683
CHEMBL1520	VARDENAFIL	4	21,263
CHEMBL1339	VARDENAFIL HYDROCHLORIDE	4	126
CHEMBL118	CELECOXIB	4	113,751
CHEMBL932	DIPYRIDAMOLE	4	52,091
CHEMBL502	DONEPEZIL	4	43,884
CHEMBL189	MILRINONE	4	20,711
CHEMBL189963	PALBOCICLIB	4	13,796
CHEMBL506247	TANNIC ACID	4	27,154
CHEMBL2103849	UDENAFIL	3	990
CHEMBL553204	ICARIIN	3	5,043
CHEMBL498485	ICARITIN	3	737
CHEMBL19224	PAPAVERINE	3	22,318
CHEMBL1928262	GISADENAFIL	2	1,197
CHEMBL4210847	PF-00489791	2	213
CHEMBL591501	PF-03049423	2	631
CHEMBL8184	CARTAZOLATE	2
CHEMBL34431	CILOSTAMIDE	2
CHEMBL356323	CIPAMFYLLINE	2
CHEMBL2110680	ISOMAZOLE	2
CHEMBL4297518	MIRODENAFIL	2
CHEMBL63	ROLIPRAM	2
CHEMBL286020	SULMAZOLE	2
CHEMBL28079	ZAPRINAST	2
CHEMBL2180408	JNJ-42396302	1
CHEMBL3770459	LENRISPODUN PHOSPHATE	1

PharmGKB: 1 entry (CPIC guideline: no)

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 (17 total), top 17:

Ligand	Action	Affinity	Parameter
compound 53 [PMID: 19631533]	Inhibition	10.3	pIC50
vardenafil	Inhibition	9.7	pIC50
T0156	Inhibition	9.5	pIC50
simenafil	Inhibition	9.21	pIC50
PF-00489791	Inhibition	9.15	pIC50
sildenafil	Inhibition	9.0	pIC50
gisadenafil	Inhibition	8.9	pIC50
tunodafil	Inhibition	8.7	pIC50
tadalafil	Inhibition	8.52	pIC50
udenafil	Inhibition	8.08	pIC50
milrinone	Inhibition	7.31	pIC50
SCH51866	Inhibition	7.2	pIC50
mirodenafil	Inhibition	7.0	pIC50
zaprinast	Inhibition	6.8	pIC50
compound 3m [PMID: 32603117]	Inhibition	6.43	pIC50
icariin	Inhibition	5.23	pIC50
ibudilast	Inhibition	3.99	pIC50

Binding affinities (BindingDB)

1965 measured of 2290 human assays (2524 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-(4-(aminomethyl)piperidin-1-yl)-1-(2-ethoxyethyl)-3-ethyl-N-(4-methylpyridin-2-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine	IC50	0.007 nM
1-(2-ethoxyethyl)-3-ethyl-N7-(4-methylpyridin-2-yl)-N5-(piperidin-4-ylmethyl)-1H-pyrazolo[4,3-d]pyrimidine-5,7-diamine	IC50	0.01 nM
CHEMBL1916488	IC50	0.01 nM
CHEMBL1916483	IC50	0.01 nM
CHEMBL1916486	IC50	0.02 nM
CHEMBL1916485	IC50	0.02 nM
CHEMBL4759667	IC50	0.025 nM
2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-[(3-chloro-4-methoxyphenyl)methoxy]-N-(pyridin-2-ylmethyl)pyrimidine-5-carboxamide	IC50	0.028 nM	US-8980904: Heterocyclic substituted pyrimidine compound
1-[9-(3-Chloro-4-methoxy-benzylamino)-3-ethyl-3H-2,3,4,7,8-pentaaza-cyclopenta[a]naphthalen-6-yl]-piperidine-4-carboxylic acid	IC50	0.03 nM
CHEMBL1916487	IC50	0.04 nM
CHEMBL1916476	IC50	0.04 nM
CHEMBL245388	IC50	0.05 nM
4-(3-Chloro-4-methoxy-benzylamino)-8-ethyl-3-hydroxymethyl-quinoline-6-carbonitrile	IC50	0.05 nM
1-(1-(2-ethoxyethyl)-3-methyl-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)piperidine-4-carboxylic acid	IC50	0.05 nM
CHEMBL1916482	IC50	0.05 nM
CHEMBL1916303	IC50	0.05 nM
CHEMBL1916293	IC50	0.05 nM
CHEMBL1916489	IC50	0.06 nM
5-(4-(aminomethyl)piperidin-1-yl)-1-(2-ethoxyethyl)-3-methyl-N-(4-methylpyridin-2-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine	IC50	0.07 nM
(1-(1-(2-ethoxyethyl)-3-ethyl-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)piperidin-4-yl)methanol	IC50	0.07 nM
1-(2-ethoxyethyl)-3-ethyl-N-phenyl-5-(piperazin-1-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine	IC50	0.07 nM
2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-[(3-chloro-4-methoxyphenyl)methoxy]-N-[(4-fluorophenyl)methyl]pyrimidine-5-carboxamide	IC50	0.075 nM	US-8980904: Heterocyclic substituted pyrimidine compound
1-(1-(2-ethoxyethyl)-3-ethyl-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)piperidine-4-carboxamide	IC50	0.08 nM
1-(1-(2-ethoxyethyl)-3-ethyl-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)piperidine-3-carboxamide	IC50	0.08 nM
CHEMBL1916291	IC50	0.08 nM
1-(2-ethoxyethyl)-3-ethyl-N5-methyl-N5-(1-methylpiperidin-4-yl)-N7-(4-methylpyridin-2-yl)-1H-pyrazolo[4,3-d]pyrimidine-5,7-diamine	IC50	0.09 nM
3-ethyl-N-(4-fluorophenyl)-5-(piperazin-1-yl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine	IC50	0.09 nM
CHEMBL1916299	IC50	0.09 nM
2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-[(3-chloro-4-methoxyphenyl)methoxy]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide	IC50	0.1 nM	US-8980904: Heterocyclic substituted pyrimidine compound
1-Ethyl-3-methyl-6-(5-nitro-2-propoxy-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one	IC50	0.1 nM
N*9*-(3-Chloro-4-methoxy-benzyl)-3-ethyl-N*6*-pyridin-4-ylmethyl-3H-2,3,4,7,8-pentaaza-cyclopenta[a]naphthalene-6,9-diamine	IC50	0.1 nM
CHEMBL1916290	IC50	0.1 nM
CHEMBL1916490	IC50	0.1 nM
CHEMBL1916295	IC50	0.1 nM
CHEMBL246988	IC50	0.11 nM
2-(5-azaspiro[2.4]heptan-5-yl)-N-benzyl-4-[(3-chloro-4-methoxyphenyl)methoxy]pyrimidine-5-carboxamide	IC50	0.119 nM	US-8980904: Heterocyclic substituted pyrimidine compound
CHEMBL3936651	IC50	0.13 nM
CHEMBL1916481	IC50	0.13 nM
3-Benzo[1,3]dioxol-5-yl-2-(5-pyridin-3-yl-furan-2-carbonyl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one	KI	0.15 nM
CHEMBL394886	IC50	0.151 nM
CHEMBL391333	IC50	0.151 nM
(E)-2-(5-((4-(2-hydroxyethyl)piperidin-1-yl)sulfonyl)-2-propoxyphenyl)-5-methyl-4-oxo-7-propyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde oxime	IC50	0.16 nM	US-11192871: 5-hydroxytryptamine receptor 7 activity modulators and their method of use
2-[5-[4-(2-hydroxyethyl)piperidin-1-yl]sulfonyl-2-propoxycyclohexa-1,3-dien-1-yl]-6-[(E)-hydroxyiminomethyl]-5-methyl-7-propyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one	IC50	0.16 nM	US-12351585: 2-phenyl-3,4-dihydropyrrolo[2,1-f] [1,2,4]triazinone derivatives as phosphodiesterase inhibitors and uses thereof
2-(3-azabicyclo[3.1.0]hexan-3-yl)-N-benzyl-4-[(3-chloro-4-methoxyphenyl)methoxy]pyrimidine-5-carboxamide	IC50	0.172 nM	US-8980904: Heterocyclic substituted pyrimidine compound
{4-[3-(1-Methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy-benzenesulfonyl]-piperazin-1-ylmethyl}-phosphonic acid monoethyl ester	IC50	0.18 nM
3-(4-(3-hydroxypropyl)piperazin-1-yl)-1-(2-propoxyethyl)-7-(6-methoxypyridin-3-yl)pyrido[3,4-b]pyrazin-2(1H)-one	IC50	0.18 nM
2-(6-azaspiro[2.5]octan-6-yl)-4-[(3-chloro-4-methoxyphenyl)methoxy]-N-(pyridin-2-ylmethyl)pyrimidine-5-carboxamide	IC50	0.186 nM	US-8980904: Heterocyclic substituted pyrimidine compound
1-(1-(2-ethoxyethyl)-3-methyl-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)piperidine-4-carboxamide	IC50	0.19 nM
CHEMBL2112876	IC50	0.2 nM
1-[3-(1,3-Dimethyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-propoxy-phenyl]-3-(4-fluoro-phenyl)-urea	IC50	0.2 nM

ChEMBL bioactivities

2415 potent at pChembl≥5 of 2617 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	IC50	0.01	nM	CHEMBL1916488
11.00	IC50	0.01	nM	CHEMBL1916483
10.96	IC50	0.011	nM	CHEMBL1098465
10.70	IC50	0.02	nM	CHEMBL1916486
10.70	IC50	0.02	nM	CHEMBL1916485
10.70	IC50	0.02	nM	CHEMBL1916475
10.60	IC50	0.025	nM	CHEMBL4759667
10.55	IC50	0.028	nM	CHEMBL3654363
10.54	IC50	0.029	nM	VARDENAFIL
10.52	IC50	0.03	nM	CHEMBL410215
10.40	IC50	0.04	nM	CHEMBL569481
10.40	IC50	0.04	nM	CHEMBL1094365
10.40	IC50	0.04	nM	CHEMBL1916487
10.40	IC50	0.04	nM	CHEMBL1916476
10.36	IC50	0.044	nM	CHEMBL4062273
10.30	IC50	0.05	nM	CHEMBL584270
10.30	IC50	0.05	nM	CHEMBL567470
10.30	IC50	0.05	nM	CHEMBL1094249
10.30	IC50	0.05	nM	CHEMBL38735
10.30	IC50	0.05	nM	CHEMBL1916482
10.30	IC50	0.05	nM	CHEMBL1916303
10.30	IC50	0.05	nM	CHEMBL1916293
10.30	IC50	0.05	nM	CHEMBL1916292
10.25	IC50	0.056	nM	CHEMBL4062273
10.23	IC50	0.059	nM	CHEMBL4072903
10.22	IC50	0.06	nM	CHEMBL565305
10.22	IC50	0.06	nM	CHEMBL1916489
10.15	IC50	0.07	nM	CHEMBL551052
10.15	IC50	0.07	nM	CHEMBL5942848
10.15	IC50	0.07	nM	CHEMBL568839
10.15	IC50	0.07	nM	CHEMBL585918
10.15	IC50	0.07	nM	CHEMBL1094544
10.15	IC50	0.07	nM	CHEMBL1098466
10.15	IC50	0.07	nM	CHEMBL1097506
10.15	IC50	0.07	nM	CHEMBL1095121
10.13	IC50	0.074	nM	CHEMBL5723336
10.12	IC50	0.075	nM	CHEMBL3654365
10.10	IC50	0.08	nM	CHEMBL566598
10.10	IC50	0.08	nM	CHEMBL1097823
10.10	IC50	0.08	nM	CHEMBL1098141
10.10	IC50	0.08	nM	CHEMBL1916291
10.06	IC50	0.087	nM	CHEMBL1094191
10.05	IC50	0.09	nM	CHEMBL566367
10.05	IC50	0.09	nM	CHEMBL1095406
10.05	IC50	0.09	nM	CHEMBL1916299
10.00	IC50	0.1	nM	CHEMBL3654362
10.00	IC50	0.1	nM	CHEMBL5081214
10.00	IC50	0.1	nM	CHEMBL567471
10.00	IC50	0.1	nM	CHEMBL344018
10.00	IC50	0.1	nM	CHEMBL1916290

PubChem BioAssay actives

2111 with measured affinity, of 3566 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-[13-[(3-chloro-4-methoxyphenyl)methylamino]-5-ethyl-4,5,7,11,12-pentazatricyclo[7.4.0.02,6]trideca-1,3,6,8,10,12-hexaen-10-yl]piperidine-4-carboxylic acid	157951: Inhibition of Phosphodiesterase 5 from human platelets	ic50	<0.0001	uM
5-[4-(aminomethyl)piperidin-1-yl]-1-(2-ethoxyethyl)-3-ethyl-N-(4-methyl-2-pyridinyl)pyrazolo[4,5-d]pyrimidin-7-amine	481330: Inhibition of PDE5 in human platelet by assessed as hydrolysis of [3H]cGMP scintillation proximity assay	ic50	<0.0001	uM
7-(6-methoxy-3-pyridinyl)-1-(2-propoxyethyl)-3-(pyridin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one	446781: Inhibition of PDE5	ic50	<0.0001	uM
Vardenafil	1704612: Inhibition of human platelets derived PDE5 using [3H]-cGMP as substrate incubated for 60 min by scintillation proximity assay	ic50	<0.0001	uM
1-[1-(2-ethoxyethyl)-3-ethyl-7-[(4-methyl-2-pyridinyl)amino]pyrazolo[4,5-d]pyrimidin-5-yl]piperidine-4-carboxylic acid	481330: Inhibition of PDE5 in human platelet by assessed as hydrolysis of [3H]cGMP scintillation proximity assay	ic50	<0.0001	uM
2-[2-ethoxy-5-[(1-imino-1-oxo-1,4-thiazinan-4-yl)sulfonyl]phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1704612: Inhibition of human platelets derived PDE5 using [3H]-cGMP as substrate incubated for 60 min by scintillation proximity assay	ic50	<0.0001	uM
1-(2-ethoxyethyl)-3-ethyl-7-N-(4-methyl-2-pyridinyl)-5-N-(piperidin-4-ylmethyl)pyrazolo[4,5-d]pyrimidine-5,7-diamine	481330: Inhibition of PDE5 in human platelet by assessed as hydrolysis of [3H]cGMP scintillation proximity assay	ic50	<0.0001	uM
8-[(4-hydroxycyclohexyl)amino]-3-(6-methoxy-3-pyridinyl)-5-(2-propoxyethyl)pyrimido[5,4-c]pyridazin-6-one	630828: Inhibition of PDE5	ic50	<0.0001	uM
2-[1-[3-(6-methoxy-3-pyridinyl)-6-oxo-5-(2-propoxyethyl)pyrimido[5,4-c]pyridazin-8-yl]piperidin-4-yl]acetic acid	630828: Inhibition of PDE5	ic50	<0.0001	uM
1-[3-(6-methoxy-3-pyridinyl)-6-oxo-5-(2-propoxyethyl)pyrimido[5,4-c]pyridazin-8-yl]piperidine-4-carboxylic acid	630828: Inhibition of PDE5	ic50	<0.0001	uM
3-[[3-(6-methoxy-3-pyridinyl)-6-oxo-5-(2-propoxyethyl)pyrimido[5,4-c]pyridazin-8-yl]amino]cyclohexane-1-carboxylic acid	630828: Inhibition of PDE5	ic50	<0.0001	uM
8-[(4-hydroxycyclohexyl)amino]-3-(6-methoxy-3-pyridinyl)-5-[2-(2,2,2-trifluoroethoxy)ethyl]pyrimido[5,4-c]pyridazin-6-one	630828: Inhibition of PDE5	ic50	<0.0001	uM
4-[[3-(6-methoxy-3-pyridinyl)-6-oxo-5-(2-propoxyethyl)pyrimido[5,4-c]pyridazin-8-yl]amino]cyclohexane-1-carboxylic acid	630828: Inhibition of PDE5	ic50	<0.0001	uM
cis-(1S,2R)-2-[[3-(6-methoxy-3-pyridinyl)-6-oxo-5-(2-propoxyethyl)pyrimido[5,4-c]pyridazin-8-yl]amino]cyclohexane-1-carboxylic acid	630828: Inhibition of PDE5	ic50	<0.0001	uM
4-[(3-chloro-4-methoxyphenyl)methylamino]-8-ethyl-3-(hydroxymethyl)quinoline-6-carbonitrile	157947: Inhibition of phosphodiesterase 5 from human platelets	ic50	0.0001	uM
3-ethyl-5-[(3R)-3-methylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]pyrazolo[4,5-d]pyrimidin-7-amine	481312: Inhibition of PDE5	ic50	0.0001	uM
3-methyl-5-[(3R)-3-methylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]pyrazolo[4,5-d]pyrimidin-7-amine	481312: Inhibition of PDE5	ic50	0.0001	uM
1-[1-(2-ethoxyethyl)-3-ethyl-7-[(4-methyl-2-pyridinyl)amino]pyrazolo[4,5-d]pyrimidin-5-yl]piperidine-3-carboxamide	481330: Inhibition of PDE5 in human platelet by assessed as hydrolysis of [3H]cGMP scintillation proximity assay	ic50	0.0001	uM
3-ethyl-N-(4-fluorophenyl)-5-piperazin-1-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]pyrazolo[4,5-d]pyrimidin-7-amine	481312: Inhibition of PDE5	ic50	0.0001	uM
[1-[1-(2-ethoxyethyl)-3-ethyl-7-[(4-methyl-2-pyridinyl)amino]pyrazolo[4,5-d]pyrimidin-5-yl]piperidin-4-yl]methanol	481330: Inhibition of PDE5 in human platelet by assessed as hydrolysis of [3H]cGMP scintillation proximity assay	ic50	0.0001	uM
3-(1,3-benzodioxol-5-yl)-2-(5-pyridin-3-ylfuran-2-carbonyl)-3,4-dihydro-1H-pyrrolo[3,4-b]quinolin-9-one	158117: Inhibitory activity against Phosphodiesterase 5 (PDE5) was evaluated	ki	0.0001	uM
9-[(3-chloro-4-methoxyphenyl)methylamino]-2-ethyl-1-oxo-3H-pyrrolo[3,4-b]quinoline-7-carbonitrile	1465725: Inhibition of human recombinant PDE5A1 using FAM-labelled cGMP as substrate after 60 mins by fluorescence polarization assay	ic50	0.0001	uM
3-(2-ethoxyethylamino)-7-(6-methoxy-3-pyridinyl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2-one	446781: Inhibition of PDE5	ic50	0.0001	uM
3-[(4-hydroxycyclohexyl)amino]-7-(6-methoxy-3-pyridinyl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2-one	446781: Inhibition of PDE5	ic50	0.0001	uM
3-[[(2R)-2-hydroxypropyl]amino]-7-(6-methoxy-3-pyridinyl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2-one	446781: Inhibition of PDE5	ic50	0.0001	uM
3-[[(2S)-2-hydroxypropyl]amino]-7-(6-methoxy-3-pyridinyl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2-one	446781: Inhibition of PDE5	ic50	0.0001	uM
3-[[(2R)-1-hydroxypropan-2-yl]amino]-7-(6-methoxy-3-pyridinyl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2-one	446781: Inhibition of PDE5	ic50	0.0001	uM
2-[[7-(6-methoxy-3-pyridinyl)-2-oxo-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-3-yl]amino]-N-methylacetamide	446781: Inhibition of PDE5	ic50	0.0001	uM
7-(6-methoxy-3-pyridinyl)-3-(2-morpholin-4-ylethylamino)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2-one	428473: Inhibition of PDE5	ic50	0.0001	uM
7-(6-methoxy-3-pyridinyl)-3-(oxolan-2-ylmethylamino)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2-one	446781: Inhibition of PDE5	ic50	0.0001	uM
7-(6-methoxy-3-pyridinyl)-3-(oxan-4-ylmethylamino)-1-(2-propoxyethyl)pyrido[2,3-b]pyrazin-2-one	446781: Inhibition of PDE5	ic50	0.0001	uM
7-(6-methoxy-3-pyridinyl)-3-[(2-morpholin-4-yl-2-oxoethyl)amino]-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2-one	446781: Inhibition of PDE5	ic50	0.0001	uM
3-[[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]amino]-7-(6-methoxy-3-pyridinyl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2-one	446781: Inhibition of PDE5	ic50	0.0001	uM
7-(6-methoxy-3-pyridinyl)-3-[(2-oxo-2-pyrrolidin-1-ylethyl)amino]-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2-one	446781: Inhibition of PDE5	ic50	0.0001	uM
7-(6-methoxy-3-pyridinyl)-3-[[2-(4-methylpiperazin-1-yl)-2-oxoethyl]amino]-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2-one	446781: Inhibition of PDE5	ic50	0.0001	uM
3-[[2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]amino]-7-(6-methoxy-3-pyridinyl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2-one	446781: Inhibition of PDE5	ic50	0.0001	uM
1-ethyl-3-methyl-6-(5-nitro-2-propoxyphenyl)-5H-pyrazolo[5,4-d]pyrimidin-4-one	157942: Inhibition of Phosphodiesterase 5 from human	ic50	0.0001	uM
(2R,8R)-2-(1,3-benzodioxol-5-yl)-6-[2-(1-benzylpiperidin-4-yl)ethyl]-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione	2124210: Inhibition of PDE5A (unknown origin)	ic50	0.0001	uM
7-(6-methoxy-3-pyridinyl)-1-(2-propoxyethyl)-3-(pyrazin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one	446781: Inhibition of PDE5	ic50	0.0001	uM
3-ethyl-5-piperazin-1-yl-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]pyrazolo[4,5-d]pyrimidin-7-amine	481312: Inhibition of PDE5	ic50	0.0001	uM
1-(2-ethoxyethyl)-3-ethyl-N-phenyl-5-piperazin-1-ylpyrazolo[4,5-d]pyrimidin-7-amine	481330: Inhibition of PDE5 in human platelet by assessed as hydrolysis of [3H]cGMP scintillation proximity assay	ic50	0.0001	uM
1-(2-ethoxyethyl)-3-ethyl-5-N-methyl-5-N-(1-methylpiperidin-4-yl)-7-N-(4-methyl-2-pyridinyl)pyrazolo[4,5-d]pyrimidine-5,7-diamine	481330: Inhibition of PDE5 in human platelet by assessed as hydrolysis of [3H]cGMP scintillation proximity assay	ic50	0.0001	uM
5-[4-(aminomethyl)piperidin-1-yl]-1-(2-ethoxyethyl)-3-methyl-N-(4-methyl-2-pyridinyl)pyrazolo[4,5-d]pyrimidin-7-amine	481330: Inhibition of PDE5 in human platelet by assessed as hydrolysis of [3H]cGMP scintillation proximity assay	ic50	0.0001	uM
1-[1-(2-ethoxyethyl)-3-ethyl-7-[(4-methyl-2-pyridinyl)amino]pyrazolo[4,5-d]pyrimidin-5-yl]piperidine-4-carboxamide	481330: Inhibition of PDE5 in human platelet by assessed as hydrolysis of [3H]cGMP scintillation proximity assay	ic50	0.0001	uM
1-[1-(2-ethoxyethyl)-3-methyl-7-[(4-methyl-2-pyridinyl)amino]pyrazolo[4,5-d]pyrimidin-5-yl]piperidine-4-carboxylic acid	481330: Inhibition of PDE5 in human platelet by assessed as hydrolysis of [3H]cGMP scintillation proximity assay	ic50	0.0001	uM
7-(6-methoxy-3-pyridinyl)-4-(2-propan-2-yloxyethylamino)-1-(2-propoxyethyl)pyrido[4,3-d]pyrimidin-2-one	630828: Inhibition of PDE5	ic50	0.0001	uM
3-(6-methoxy-3-pyridinyl)-8-(2-morpholin-4-ylethylamino)-5-(2-propoxyethyl)pyrimido[5,4-c]pyridazin-6-one	630828: Inhibition of PDE5	ic50	0.0001	uM
3-[[3-(6-methoxy-3-pyridinyl)-6-oxo-5-(2-propoxyethyl)pyrimido[5,4-c]pyridazin-8-yl]amino]propanoic acid	630828: Inhibition of PDE5	ic50	0.0001	uM
2-[[3-(6-methoxy-3-pyridinyl)-6-oxo-5-(2-propoxyethyl)pyrimido[5,4-c]pyridazin-8-yl]amino]-2-methylpropanoic acid	630828: Inhibition of PDE5	ic50	0.0001	uM
4-[(4-hydroxycyclohexyl)amino]-7-(6-methoxy-3-pyridinyl)-1-(2-propoxyethyl)pyrido[3,2-d]pyrimidin-2-one	630828: Inhibition of PDE5	ic50	0.0001	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Sildenafil Citrate	decreases activity	6
sodium arsenite	affects expression, decreases expression, affects cotreatment, increases abundance, increases expression	4
Tadalafil	decreases activity	4
Vardenafil Dihydrochloride	decreases activity	4
Valproic Acid	decreases expression, decreases methylation, affects expression	4
Copper	increases expression, affects binding	3
Estradiol	affects expression, decreases expression, increases reaction	3
sulindac sulfone	affects binding, decreases activity	2
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression, affects response to substance, increases expression	2
Air Pollutants	increases expression, decreases expression, increases abundance	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	increases expression	2
Particulate Matter	decreases expression, increases abundance	2
afuresertib	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
sulforaphane	decreases expression	1
butyraldehyde	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	increases expression	1
pentanal	increases expression	1
avobenzone	increases expression	1
MY 5445	decreases activity	1
icariin	decreases activity	1
polydatin	decreases activity	1
malvidin	decreases activity	1

ChEMBL screening assays

509 unique, capped per target: 492 binding, 9 admet, 7 functional, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1011852	Binding	Inhibition of PDE5	Identification of potent pyrimidine inhibitors of phosphodiesterase 7 (PDE7) and their ability to inhibit T cell proliferation. — *Bioorg Med Chem Lett*
CHEMBL4021628	ADMET	Inhibition of PDE5A1 (unknown origin) at 5 uM using fluorescein-labeled cGMP as substrate preincubated for 15 mins followed by substrate addition measured after 30 mins by IMAP fluorescence polarization assay relative to control	Design and optimization of purine derivatives as in vivo active PDE10A inhibitors. — *Bioorg Med Chem*
CHEMBL5723295	Functional	Affinity Biochemical interaction: (inhibition of enzyme activity in cleaving radiolabelled substrate [3H]cGMP) EUB0002742aCl PDE5A	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C7DE	Abcam A-549 PDE5A KO	Cancer cell line	Male
CVCL_C7E4	Abcam HCT 116 PDE5A KO	Cancer cell line	Male
CVCL_D1TW	Abcam U-87MG PDE5A KO	Cancer cell line	Male
CVCL_TC67	HAP1 PDE5A (-)	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PDE5A across ~30M SureChEMBL compounds — explore on Sugi Predict.