Target Information

Target General Information

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Target ID

T07663 (Former ID: TTDS00296)

Target Name

Phosphodiesterase 5A (PDE5A)

Synonyms

cGMP-specific 3',5'-cyclic phosphodiesterase; PDE5A; CGMP-binding cGMP-specific phosphodiesterase; CGB-PDE

Gene Name

PDE5A

Target Type

Successful target

[1]

Disease

[+] 4 Target-related Diseases

Hypertension [ICD-11: BA00-BA04]

Innate/adaptive immunodeficiency [ICD-11: 4A00]

Sexual dysfunction [ICD-11: HA00-HA01]

Tonus and reflex abnormality [ICD-11: MB47]

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.

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BioChemical Class

Phosphoric diester hydrolase

UniProt ID

PDE5A_HUMAN

EC Number

EC 3.1.4.35

Sequence

MERAGPSFGQQRQQQQPQQQKQQQRDQDSVEAWLDDHWDFTFSYFVRKATREMVNAWFAE
RVHTIPVCKEGIRGHTESCSCPLQQSPRADNSAPGTPTRKISASEFDRPLRPIVVKDSEG
TVSFLSDSEKKEQMPLTPPRFDHDEGDQCSRLLELVKDISSHLDVTALCHKIFLHIHGLI
SADRYSLFLVCEDSSNDKFLISRLFDVAEGSTLEEVSNNCIRLEWNKGIVGHVAALGEPL
NIKDAYEDPRFNAEVDQITGYKTQSILCMPIKNHREEVVGVAQAINKKSGNGGTFTEKDE
KDFAAYLAFCGIVLHNAQLYETSLLENKRNQVLLDLASLIFEEQQSLEVILKKIAATIIS
FMQVQKCTIFIVDEDCSDSFSSVFHMECEELEKSSDTLTREHDANKINYMYAQYVKNTME
PLNIPDVSKDKRFPWTTENTGNVNQQCIRSLLCTPIKNGKKNKVIGVCQLVNKMEENTGK
VKPFNRNDEQFLEAFVIFCGLGIQNTQMYEAVERAMAKQMVTLEVLSYHASAAEEETREL
QSLAAAVVPSAQTLKITDFSFSDFELSDLETALCTIRMFTDLNLVQNFQMKHEVLCRWIL
SVKKNYRKNVAYHNWRHAFNTAQCMFAALKAGKIQNKLTDLEILALLIAALSHDLDHRGV
NNSYIQRSEHPLAQLYCHSIMEHHHFDQCLMILNSPGNQILSGLSIEEYKTTLKIIKQAI
LATDLALYIKRRGEFFELIRKNQFNLEDPHQKELFLAMLMTACDLSAITKPWPIQQRIAE
LVATEFFDQGDRERKELNIEPTDLMNREKKNKIPSMQVGFIDAICLQLYEALTHVSEDCF
PLLDGCRKNRQKWQALAEQQEKMLINGESGQAKRN

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3D Structure

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PDB

HIT2.0 ID

T32BH6

Drugs and Modes of Action

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Approved Drug(s)

[+] 7 Approved Drugs

Avanafil

Drug Info

Approved

Erectile dysfunction

[2], [3]

Dipyridamole

Drug Info

Approved

Hypertension

[4], [5]

Papaverine

Drug Info

Approved

Spasm

[6]

Rhucin

Drug Info

Approved

Hereditary angioedema

[7], [8]

Tadalafil

Drug Info

Approved

Erectile dysfunction

[9], [10]

Udenafil

Drug Info

Approved

Erectile dysfunction

[11]

Vardenafil

Drug Info

Approved

Erectile dysfunction

[10], [12]

Clinical Trial Drug(s)

[+] 3 Clinical Trial Drugs

EXISULIND

Drug Info

Phase 3

Colorectal cancer

[13]

PF-489791

Drug Info

Phase 2

Raynaud disease

[14]

UK-371800

Drug Info

Phase 1

Erectile dysfunction

[15]

Discontinued Drug(s)

[+] 9 Discontinued Drugs

BRL-61063

Drug Info

Discontinued in Phase 2

Allergy

[16]

DASANTAFIL

Drug Info

Discontinued in Phase 2

Erectile dysfunction

[17]

E-4021

Drug Info

Discontinued in Phase 2

Cardiovascular disease

[18]

EMR-62203

Drug Info

Discontinued in Phase 2

Erectile dysfunction

[19]

SINITRODIL

Drug Info

Discontinued in Phase 2

Angina pectoris

[20]

SLX-2101

Drug Info

Discontinued in Phase 2

Raynaud disease

[21]

UK-369003

Drug Info

Discontinued in Phase 1/2

Erectile dysfunction

[22], [23]

FR-229934

Drug Info

Terminated

Erectile dysfunction

[24]

SKF-96231

Drug Info

Terminated

Asthma

[25]

Mode of Action

[+] 3 Modes of Action

Modulator

[+] 5 Modulator drugs

Avanafil

Drug Info

[26]

Dipyridamole

Drug Info

[27]

EXISULIND

Drug Info

[36]

SINITRODIL

Drug Info

[26]

RWJ-387273

Drug Info

[57]

Inhibitor

[+] 40 Inhibitor drugs

Papaverine

Drug Info

[28]

Rhucin

Drug Info

[29], [30], [31], [32]

Tadalafil

Drug Info

[33], [32], [34]

Udenafil

Drug Info

[35]

ICARIIN

Drug Info

[37]

PF-489791

Drug Info

[38]

UK-371800

Drug Info

[15]

BRL-61063

Drug Info

[39]

DASANTAFIL

Drug Info

[26]

E-4021

Drug Info

[40]

EMR-62203

Drug Info

[41]

SLX-2101

Drug Info

[42]

UK-369003

Drug Info

[43], [44]

FR-229934

Drug Info

[45]

IMAZODAN

Drug Info

[46]

SKF-96231

Drug Info

[47]

Trequinsin

Drug Info

[48]

ZAPRINAST

Drug Info

[49]

3,7-Bis(2-hydroxyethyl)icaritin

Drug Info

[37]

7-(2-Hydroxyethyl)-3-O-rhamnosylicariin

Drug Info

[37]

8-prenylapigenin

Drug Info

[37]

8-prenylquercetin

Drug Info

[37]

Aom-0890

Drug Info

[50]

Benzo[1,3]dioxol-5-ylmethyl-quinazolin-4-yl-amine

Drug Info

[51]

Cartazolate

Drug Info

[52]

CKD-533

Drug Info

[50]

Gamma-Glutamyl[S-(2-Iodobenzyl)Cysteinyl]Glycine

Drug Info

[53]

Guanosine-5'-Monophosphate

Drug Info

[53]

Icariside II

Drug Info

[37]

isobutylmethylxanthine

Drug Info

[54]

KURAIDIN

Drug Info

[55]

KURARINOL

Drug Info

[55]

LORNEIC ACID A

Drug Info

[56]

ROLIPRAM

Drug Info

[51]

SCH-57726

Drug Info

[58]

SCH51866

Drug Info

[59]

SOPHOFLAVESCENOL

Drug Info

[55]

SOPHORAFLAVANONE B

Drug Info

[37]

T0156

Drug Info

[60]

TPN-729

Drug Info

[50]

Binder

[+] 1 Binder drugs

Vardenafil

Drug Info

[1]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 2 KEGG Pathways

Purine metabolism

cGMP-PKG signaling pathway

NetPath Pathway

[+] 1 NetPath Pathways

TGF_beta_Receptor Signaling Pathway

Reactome

[+] 1 Reactome Pathways

cGMP effects

Target-Related Models and Studies

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Target Validation

Target Validation Info

Target QSAR Model

References

Top

REF 1

The effect of vardenafil, a potent and highly selective phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction, on the cardiovascular response to exercise in patients with coronary artery disease. J Am Coll Cardiol. 2002 Dec 4;40(11):2006-12.

REF 2

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7448).

REF 3

Nat Rev Drug Discov. 2013 Feb;12(2):87-90.

REF 4

REF 5

Inhibition of platelet activation and aggregation. Handb Exp Pharmacol. 2005;(170):443-62.

REF 6

Drug information of Papaverine, 2008. eduDrugs.

REF 7

Mullard A: 2010 FDA drug approvals. Nat Rev Drug Discov. 2011 Feb;10(2):82-5.

REF 8

Recombinant human c1 inhibitor (conestat alfa): in the treatment of angioedema attacks in hereditary angioedema. BioDrugs. 2012 Oct 1;26(5):315-23.

REF 9

REF 10

Designing drugs for the treatment of female sexual dysfunction. Drug Discov Today. 2007 Sep;12(17-18):757-66.

REF 11

Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.

REF 12

REF 13

ClinicalTrials.gov (NCT00085826) A Phase III Study of the Efficacy of Taxotere/Aptosyn Versus Taxotere/Placebo in Non-Small Cell Lung Cancer Patients. U.S. National Institutes of Health.

REF 14

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025495)

REF 15

Highly potent and selective chiral inhibitors of PDE5: an illustration of Pfeiffer's rule. Bioorg Med Chem Lett. 2008 Dec 1;18(23):6033-6.

REF 16

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004678)

REF 17

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018967)

REF 18

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004019)

REF 19

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018868)

REF 20

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005482)

REF 21

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022583)

REF 22

REF 23

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800017097)

REF 24

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014897)

REF 25

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003084)

REF 26

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 27

Anti-platelet therapy: phosphodiesterase inhibitors.Br J Clin Pharmacol.2011 Oct;72(4):634-46.

REF 28

Effects of icariin on cGMP-specific PDE5 and cAMP-specific PDE4 activities. Asian J Androl. 2003 Mar;5(1):15-8.

REF 29

cGMP-hydrolytic activity and its inhibition by sildenafil in normal and failing human and mouse myocardium. J Pharmacol Exp Ther. 2009 Sep;330(3):884-91.

REF 30

Efficacy and safety of sildenafil citrate (Viagra) in men with erectile dysfunction and spinal cord injury: a review. Urology. 2002 Sep;60(2 Suppl 2):49-57.

REF 31

Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51.

REF 32

Phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction in patients with diabetes mellitus. Int J Impot Res. 2002 Dec;14(6):466-71.

REF 33

Pulmonary arterial hypertension: the most devastating vascular complication of systemic sclerosis. Rheumatology (Oxford). 2009 Jun;48 Suppl 3:iii25-31.

REF 34

Tadalafil (Cialis) for men with erectile dysfunction. Int J Clin Pract. 2002 May;56(4):300-4.

REF 35

Increased expression of the nitric oxide synthase gene and protein in corpus cavernosum by repeated dosing of udenafil in a rat model of chemical d... Asian J Androl. 2009 Jul;11(4):435-42.

REF 36

Exisulind induction of apoptosis involves guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation, and attenuated beta-catenin. Cancer Res. 2000 Jul 1;60(13):3338-42.

REF 37

Potent inhibition of human phosphodiesterase-5 by icariin derivatives. J Nat Prod. 2008 Sep;71(9):1513-7.

REF 38

Highlights of the society for medicinesresearch symposium held december 10th 2009 at the national heart and lung institute, London, UK. Drugs of the Future 2010, 35(4): 349-358.

REF 39

Inhibition of cyclic nucleotide phosphodiesterase by derivatives of 1,3-bis(cyclopropylmethyl)xanthine. J Med Chem. 1994 Feb 18;37(4):476-85.

REF 40

Potency and mechanism of action of E4021, a type 5 phosphodiesterase isozyme-selective inhibitor, on the photoreceptor phosphodiesterase depend on the state of activation of the enzyme. Mol Pharmacol. 1999 Mar;55(3):508-14.

REF 41

WO patent application no. 2006,0180,88, Use of a pde 5 inhibitor for treating and preventing hypopigmentary disorders.

REF 42

Novel phosphodiesterase-5 (PDE5) inhibitors in the alleviation of erectile dysfunction due to diabetes and ageing-induced oxidative stress. Expert Opin Investig Drugs. 2008 Jun;17(6):855-64.

REF 43

Pfizer. Product Development Pipeline. March 31 2009.

REF 44

ClinicalTrials.gov (NCT00457457) Pfizer. Report of Pfizer. September 2 2008.

REF 45

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014897)

REF 46

Cardiotonic agents. 1. 4,5-Dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3 (2H)-pyridazinones: novel positive inotropic agents for the treatment of conges... J Med Chem. 1984 Sep;27(9):1099-101.

REF 47

Analogue-based Drug Discovery II. Janos Fischer,C. Robin Ganellin. Page(150).

REF 48

Inhibition of cyclic adenosine-3',5'-monophosphate phosphodiesterase from vascular smooth muscle by rolipram analogues. J Med Chem. 1989 Jul;32(7):1450-7.

REF 49

4-(3-Chloro-4-methoxybenzyl)aminophthalazines: synthesis and inhibitory activity toward phosphodiesterase 5. J Med Chem. 2000 Jun 29;43(13):2523-9.

REF 50

REF 51

Cyclic GMP phosphodiesterase inhibitors. 2. Requirement of 6-substitution of quinazoline derivatives for potent and selective inhibitory activity. J Med Chem. 1994 Jun 24;37(13):2106-11.

REF 52

Substituted pyrazolopyridines as potent and selective PDE5 inhibitors: potential agents for treatment of erectile dysfunction. J Med Chem. 2001 Mar 29;44(7):1025-7.

REF 53

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 54

The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.

REF 55

A prenylated flavonol, sophoflavescenol: a potent and selective inhibitor of cGMP phosphodiesterase 5. Bioorg Med Chem Lett. 2002 Sep 2;12(17):2313-6.

REF 56

Lorneic acids, trialkyl-substituted aromatic acids from a marine-derived actinomycete. J Nat Prod. 2009 Nov;72(11):2046-8.

REF 57

DOI: 10.1021/op060099f

REF 58

The Gif system as a tool in medicinal chemistry: The oxidation of Sch 57726 under GoAggIII conditions, Bioorg. Med. Chem. Lett. 7(11):1381-1386 (1997).

REF 59

Antiplatelet and antiproliferative effects of SCH 51866, a novel type 1 and type 5 phosphodiesterase inhibitor. J Cardiovasc Pharmacol. 1996 Dec;28(6):862-9.

REF 60

Enzymological and pharmacological profile of T-0156, a potent and selective phosphodiesterase type 5 inhibitor. Eur J Pharmacol. 2002 Dec 5;456(1-3):91-8.

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