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phosphodiesterase 5A

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 1304

Nomenclature: phosphodiesterase 5A

Abbreviated Name: PDE5A

Family: Phosphodiesterases, 3',5'-cyclic nucleotide (PDEs)

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 875 4q26 PDE5A phosphodiesterase 5A
Mouse - 865 3 G1 Pde5a phosphodiesterase 5A, cGMP-specific
Rat - 833 2q42 Pde5a phosphodiesterase 5A
Previous and Unofficial Names Click here for help
cGMP-binding cGMP specific phosphodiesterase 5A2 | PDE5A2 | PDE5A1 | phosphodiesterase 5A, cGMP-specific
Database Links Click here for help
Alphafold O76074 (Hs), Q8CG03 (Mm), O54735 (Rn)
BRENDA 3.1.4.17
CATH/Gene3D 3.30.450.40, 1.10.1300.10
ChEMBL Target CHEMBL1827 (Hs), CHEMBL4567 (Rn)
DrugBank Target O76074 (Hs)
Ensembl Gene ENSG00000138735 (Hs), ENSMUSG00000053965 (Mm), ENSRNOG00000014443 (Rn)
Entrez Gene 8654 (Hs), 242202 (Mm), 171115 (Rn)
Human Protein Atlas ENSG00000138735 (Hs)
KEGG Enzyme 3.1.4.17
KEGG Gene hsa:8654 (Hs), mmu:242202 (Mm), rno:171115 (Rn)
OMIM 603310 (Hs)
Pharos O76074 (Hs)
SynPHARM 13777 (in complex with sildenafil)
79448 (in complex with tadalafil)
79463 (in complex with vardenafil)
UniProtKB O76074 (Hs), Q8CG03 (Mm), O54735 (Rn)
Wikipedia PDE5A (Hs)
Enzyme Reaction Click here for help
EC Number: 3.1.4.17
Activators (Human)
Protein kinase A, protein kinase G  [6]
Rank order of affinity (Human)
cyclic GMP > cyclic AMP

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 53 [PMID: 19631533] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 10.3 pIC50 9
⤷ pIC50 10.3 (IC50 5x10-11 M) [9]
vardenafil Small molecule or natural product Approved drug Primary target of this compound Ligand has a PDB structure Hs Inhibition 9.7 pIC50 3
⤷ pIC50 9.7 (IC50 2x10-10 M) [3]
T0156 Small molecule or natural product Hs Inhibition 9.5 pIC50 11
⤷ pIC50 9.5 (IC50 3.16x10-10 M) [11]
TPN171 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 9.2 pIC50 18
⤷ pIC50 9.2 (IC50 6.2x10-10 M) [18]
PF-00489791 Small molecule or natural product Primary target of this compound Hs Inhibition 9.1 pIC50 5
⤷ pIC50 9.1 (IC50 7.1x10-10 M) [5]
gisadenafil Small molecule or natural product Hs Inhibition 8.9 pIC50 13
⤷ pIC50 8.9 [13]
sildenafil Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.4 – 9.0 pIC50 14,17
⤷ pIC50 8.4 – 9.0 (IC50 3.9x10-9 – 1x10-9 M) [14,17]
tunodafil Small molecule or natural product Hs Inhibition 8.7 pIC50 4
⤷ pIC50 8.7 (IC50 2x10-9 M) [4]
tadalafil Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.5 pIC50 12
⤷ pIC50 8.5 (IC50 3x10-9 M) [12]
udenafil Small molecule or natural product Approved drug Hs Inhibition 8.1 pIC50 7
⤷ pIC50 8.1 (IC50 8.25x10-9 M) [7]
Description: Inhibition of PDE5 activity in human platelets
milrinone Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.3 pIC50
⤷ pIC50 7.3 (IC50 4.91x10-8 M)
SCH51866 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.2 pIC50 15
⤷ pIC50 7.2 (IC50 6.31x10-8 M) [15]
zaprinast Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.8 pIC50 14
⤷ pIC50 6.8 (IC50 1.58x10-7 M) [14]
compound 3m [PMID: 32603117] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.4 pIC50 19
⤷ pIC50 6.4 (IC50 3.7x10-7 M) [19]
Description: Biochemical inhibition of recombinant PDE5A1 catalytic domain (aa535–860).
ibudilast Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 4.0 pIC50 2
⤷ pIC50 4.0 (IC50 1.03x10-4 M) [2]
nitrosoprodenafil Small molecule or natural product Hs Inhibition - - 16
⤷ [16]
icariside II Small molecule or natural product N/A Inhibition - - 8
⤷ [8]
View species-specific inhibitor tables
Inhibitor Comments
Tadalafil is selective for PDE5A over other PDEs tested [12]. Vardenafil is also selective for PDE5A, the next closest inhibitory effect is on PDE3 (IC50 1nM) [3].
Immunopharmacology Comments
The role of PDE5A in immuno-oncology is reviewed in [1].
Immuno Process Associations
Immuno Process:  T cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling
Immuno Process:  Inflammation
General Comments
PDE5 is the main cGMP-metabolizing enzyme. Three major PDE5 isoforms are described (A1, A2 and A3). PDE5 is highly expressed in vascular and bronchial smooth muscle, in renal tubules and in platelets. Clinically used PDE5 inhibitors target PDE5 in vascular muscle (to treat erectile dysfunction) and bronchial smooth muscle (to treat pulmonary arterial hypertension). PDE5 is highly expressed in cardiac tissues of experimental and human heart disease, suggesting it as a therapeutic target for cardiovascular disease via the repurposing of existing drugs (reviewed in [10]).

References

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1. Adams JL, Smothers J, Srinivasan R, Hoos A. (2015) Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov, 14 (9): 603-22. [PMID:26228631]

2. Allcock RW, Blakli H, Jiang Z, Johnston KA, Morgan KM, Rosair GM, Iwase K, Kohno Y, Adams DR. (2011) Phosphodiesterase inhibitors. Part 1: Synthesis and structure-activity relationships of pyrazolopyridine-pyridazinone PDE inhibitors developed from ibudilast. Bioorg Med Chem Lett, 21 (11): 3307-12. [PMID:21530250]

3. Boyle CD, Xu R, Asberom T, Chackalamannil S, Clader JW, Greenlee WJ, Guzik H, Hu Y, Hu Z, Lankin CM et al.. (2005) Optimization of purine based PDE1/PDE5 inhibitors to a potent and selective PDE5 inhibitor for the treatment of male ED. Bioorg Med Chem Lett, 15 (9): 2365-9. [PMID:15837326]

4. Chen X, Wang N, Liu Y, Liu Y, Zhang T, Zhu L, Wang Y, Wu C, Yang J. (2014) Yonkenafil: a novel phosphodiesterase type 5 inhibitor induces neuronal network potentiation by a cGMP-dependent Nogo-R axis in acute experimental stroke. Exp Neurol, 261: 267-77. [PMID:25064698]

5. Clerin V, Gale J, Tamimi N. (2014) Use of a tetrasubstituted pyrazolo[4,3-d]pyrimidine compound for treating diabetic nephropathy. Patent number: WO-2014064566-A1. Assignee: Pfizer Inc.. Priority date: 23/10/2012. Publication date: 01/05/2014.

6. Corbin JD, Turko IV, Beasley A, Francis SH. (2000) Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. Eur J Biochem, 267 (9): 2760-7. [PMID:10785399]

7. Doh H, Shin CY, Son M, Ko JI, Yoo M, Kim SH, Kim WB. (2002) Mechanism of erectogenic effect of the selective phosphodiesterase type 5 inhibitor, DA-8159. Arch Pharm Res, 25 (6): 873-8. [PMID:12510841]

8. Gao J, Long L, Xu F, Feng L, Liu Y, Shi J, Gong Q. (2020) Icariside II, a phosphodiesterase 5 inhibitor, attenuates cerebral ischaemia/reperfusion injury by inhibiting glycogen synthase kinase-3β-mediated activation of autophagy. Br J Pharmacol, 177 (6): 1434-1452. [PMID:31658364]

9. Hughes RO, Walker JK, Rogier DJ, Heasley SE, Blevis-Bal RM, Benson AG, Jacobsen EJ, Cubbage JW, Fobian YM, Owen DR et al.. (2009) Optimization of the aminopyridopyrazinones class of PDE5 inhibitors: discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one. Bioorg Med Chem Lett, 19 (17): 5209-13. [PMID:19631533]

10. Korkmaz-Icöz S, Radovits T, Szabó G. (2018) Targeting phosphodiesterase 5 as a therapeutic option against myocardial ischaemia/reperfusion injury and for treating heart failure. Br J Pharmacol, 175 (2): 223-231. [PMID:28213937]

11. Mochida H, Takagi M, Inoue H, Noto T, Yano K, Fujishige K, Sasaki T, Yuasa K, Kotera J, Omori K et al.. (2002) Enzymological and pharmacological profile of T-0156, a potent and selective phosphodiesterase type 5 inhibitor. Eur J Pharmacol, 456 (1-3): 91-8. [PMID:12450574]

12. Mohamed HA, Girgis NM, Wilcken R, Bauer MR, Tinsley HN, Gary BD, Piazza GA, Boeckler FM, Abadi AH. (2011) Synthesis and molecular modeling of novel tetrahydro-β-carboline derivatives with phosphodiesterase 5 inhibitory and anticancer properties. J Med Chem, 54 (2): 495-509. [PMID:21189023]

13. Rawson DJ, Ballard S, Barber C, Barker L, Beaumont K, Bunnage M, Cole S, Corless M, Denton S, Ellis D et al.. (2012) The discovery of UK-369003, a novel PDE5 inhibitor with the potential for oral bioavailability and dose-proportional pharmacokinetics. Bioorg Med Chem, 20 (1): 498-509. [PMID:22100260]

14. Turko IV, Ballard SA, Francis SH, Corbin JD. (1999) Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. Mol Pharmacol, 56 (1): 124-30. [PMID:10385692]

15. Vemulapalli S, Watkins RW, Chintala M, Davis H, Ahn HS, Fawzi A, Tulshian D, Chiu P, Chatterjee M, Lin CC et al.. (1996) Antiplatelet and antiproliferative effects of SCH 51866, a novel type 1 and type 5 phosphodiesterase inhibitor. J Cardiovasc Pharmacol, 28 (6): 862-9. [PMID:8961086]

16. Venhuis BJ, Zomer G, Hamzink M, Meiring HD, Aubin Y, de Kaste D. (2011) The identification of a nitrosated prodrug of the PDE-5 inhibitor aildenafil in a dietary supplement: a Viagra with a pop. J Pharm Biomed Anal, 54 (4): 735-41. [PMID:21145686]

17. Wang G, Liu Z, Chen T, Wang Z, Yang H, Zheng M, Ren J, Tian G, Yang X, Li L et al.. (2012) Design, synthesis, and pharmacological evaluation of monocyclic pyrimidinones as novel inhibitors of PDE5. J Med Chem, 55 (23): 10540-50. [PMID:23137303]

18. Wang Z, Jiang X, Zhang X, Tian G, Yang R, Wu J, Zou X, Liu Z, Yang X, Wu C et al.. (2019) Pharmacokinetics-Driven Optimization of 4(3 H)-Pyrimidinones as Phosphodiesterase Type 5 Inhibitors Leading to TPN171, a Clinical Candidate for the Treatment of Pulmonary Arterial Hypertension. J Med Chem, 62 (10): 4979-4990. [PMID:31021628]

19. Wu Y, Tian YJ, Le ML, Zhang SR, Zhang C, Huang MX, Jiang MY, Zhang B, Luo HB. (2020) Discovery of Novel Selective and Orally Bioavailable Phosphodiesterase-1 Inhibitors for the Efficient Treatment of Idiopathic Pulmonary Fibrosis. J Med Chem, 63 (14): 7867-7879. [PMID:32603117]

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