Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTJ0IQB)

• DTT Name: Phosphodiesterase 5A (PDE5A)
• Synonyms: cGMP-specific 3',5'-cyclic phosphodiesterase; PDE5A; CGMP-binding cGMP-specific phosphodiesterase; CGB-PDE
• Gene Name: PDE5A
• DTT Type: Successful target; [1]
• BioChemical Class: Phosphoric diester hydrolase
• UniProt ID: PDE5A_HUMAN
• TTD ID: T07663
• EC Number: EC 3.1.4.35
• Sequence:
  MERAGPSFGQQRQQQQPQQQKQQQRDQDSVEAWLDDHWDFTFSYFVRKATREMVNAWFAE
  RVHTIPVCKEGIRGHTESCSCPLQQSPRADNSAPGTPTRKISASEFDRPLRPIVVKDSEG
  TVSFLSDSEKKEQMPLTPPRFDHDEGDQCSRLLELVKDISSHLDVTALCHKIFLHIHGLI
  SADRYSLFLVCEDSSNDKFLISRLFDVAEGSTLEEVSNNCIRLEWNKGIVGHVAALGEPL
  NIKDAYEDPRFNAEVDQITGYKTQSILCMPIKNHREEVVGVAQAINKKSGNGGTFTEKDE
  KDFAAYLAFCGIVLHNAQLYETSLLENKRNQVLLDLASLIFEEQQSLEVILKKIAATIIS
  FMQVQKCTIFIVDEDCSDSFSSVFHMECEELEKSSDTLTREHDANKINYMYAQYVKNTME
  PLNIPDVSKDKRFPWTTENTGNVNQQCIRSLLCTPIKNGKKNKVIGVCQLVNKMEENTGK
  VKPFNRNDEQFLEAFVIFCGLGIQNTQMYEAVERAMAKQMVTLEVLSYHASAAEEETREL
  QSLAAAVVPSAQTLKITDFSFSDFELSDLETALCTIRMFTDLNLVQNFQMKHEVLCRWIL
  SVKKNYRKNVAYHNWRHAFNTAQCMFAALKAGKIQNKLTDLEILALLIAALSHDLDHRGV
  NNSYIQRSEHPLAQLYCHSIMEHHHFDQCLMILNSPGNQILSGLSIEEYKTTLKIIKQAI
  LATDLALYIKRRGEFFELIRKNQFNLEDPHQKELFLAMLMTACDLSAITKPWPIQQRIAE
  LVATEFFDQGDRERKELNIEPTDLMNREKKNKIPSMQVGFIDAICLQLYEALTHVSEDCF
  PLLDGCRKNRQKWQALAEQQEKMLINGESGQAKRN
• 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.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  cGMP-PKG signaling pathway (hsa04022)
• Reactome Pathway: cGMP effects (R-HSA-418457)

Molecular Interaction Atlas (MIA) of This DTT

7 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Avanafil	DM75CXN	Erectile dysfunction	HA01.1	Approved	[2]
Dipyridamole	DMXY30O	Atrial fibrillation	BC81.3	Approved	[3]
Papaverine	DMCA9QP	Brain ischaemia	8B1Z	Approved	[4]
Rhucin	DM3ADGP	Erectile dysfunction	HA01.1	Approved	[5]
Tadalafil	DMJZHT1	Benign prostatic hyperplasia	GA90	Approved	[6]
Udenafil	DM1IQRP	Erectile dysfunction	HA01.1	Approved	[7]
Vardenafil	DMTBGW8	Cystic fibrosis	CA25	Approved	[1]

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
EXISULIND	DMBY56U	Colorectal cancer	2B91.Z	Phase 3	[8]
ICARIIN	DMOJQGT	N. A.	N. A.	Phase 3	[9]
PF-489791	DM3C8GQ	Chronic obstructive pulmonary disease	CA22	Phase 2	[10]
UK-371800	DMI8795	Erectile dysfunction	HA01.1	Phase 1	[11]

12 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BRL-61063	DMV3Y8R	Allergy	4A80-4A85	Discontinued in Phase 2	[12]
DASANTAFIL	DMOWIGC	Erectile dysfunction	HA01.1	Discontinued in Phase 2	[2]
E-4021	DMWIA56	Cardiovascular disease	BA00-BE2Z	Discontinued in Phase 2	[13]
EMR-62203	DMIQRJW	Erectile dysfunction	HA01.1	Discontinued in Phase 2	[14]
SINITRODIL	DMMZ2JT	Angina pectoris	BA40	Discontinued in Phase 2	[2]
SLX-2101	DM1J0YB	Erectile dysfunction	HA01.1	Discontinued in Phase 2	[15]
UK-369003	DMHXRZF	Erectile dysfunction	HA01.1	Discontinued in Phase 1/2	[16]
FR-229934	DMT6R8I	Erectile dysfunction	HA01.1	Terminated	[17]
IMAZODAN	DMWTFO3	N. A.	N. A.	Terminated	[18]
SKF-96231	DMS2M58	Asthma	CA23	Terminated	[19]
Trequinsin	DMQRSMD	N. A.	N. A.	Terminated	[20]
ZAPRINAST	DMGH3T5	N. A.	N. A.	Terminated	[21]

23 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
3,7-Bis(2-hydroxyethyl)icaritin	DMQADXL	Discovery agent	N.A.	Investigative	[9]
7-(2-Hydroxyethyl)-3-O-rhamnosylicariin	DMBIY98	Discovery agent	N.A.	Investigative	[9]
8-prenylapigenin	DM2VC0E	Discovery agent	N.A.	Investigative	[9]
8-prenylquercetin	DMZC1SV	Discovery agent	N.A.	Investigative	[9]
Aom-0890	DMT4I2W	Erectile dysfunction	HA01.1	Investigative	[22]
Benzo[1,3]dioxol-5-ylmethyl-quinazolin-4-yl-amine	DM067NL	Discovery agent	N.A.	Investigative	[23]
Cartazolate	DMSKT8G	Discovery agent	N.A.	Investigative	[24]
CKD-533	DMH204Y	Erectile dysfunction	HA01.1	Investigative	[22]
Gamma-Glutamyl[S-(2-Iodobenzyl)Cysteinyl]Glycine	DMHNJDE	Discovery agent	N.A.	Investigative	[25]
Guanosine-5'-Monophosphate	DM3SLZK	Discovery agent	N.A.	Investigative	[25]
Icariside II	DM3DB8X	Discovery agent	N.A.	Investigative	[9]
isobutylmethylxanthine	DM46F5X	Discovery agent	N.A.	Investigative	[26]
KURAIDIN	DMLDUJ1	Discovery agent	N.A.	Investigative	[27]
KURARINOL	DMRV5YE	Discovery agent	N.A.	Investigative	[27]
LORNEIC ACID A	DM0ECUK	Discovery agent	N.A.	Investigative	[28]
ROLIPRAM	DMJ03UM	Discovery agent	N.A.	Investigative	[23]
RWJ-387273	DM28IKN	Discovery agent	N.A.	Investigative	[29]
SCH-57726	DMDK8TR	Discovery agent	N.A.	Investigative	[30]
SCH51866	DMCWSJP	Discovery agent	N.A.	Investigative	[31]
SOPHOFLAVESCENOL	DM8Y1S7	Discovery agent	N.A.	Investigative	[27]
SOPHORAFLAVANONE B	DMUVKX5	Discovery agent	N.A.	Investigative	[9]
T0156	DMZE9TW	Discovery agent	N.A.	Investigative	[32]
TPN-729	DMW9G7H	Erectile dysfunction	HA01.1	Investigative	[22]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rectal cancer	2C82	Rectal colon tissue	1.60E-01	-0.25	-0.99
Asthma	CA23	Nasal and bronchial airway	3.24E-05	-0.07	-0.17
Breast cancer	2C82	Breast tissue	9.41E-20	-0.28	-0.69

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Phosphodiesterase 5A (PDE5A) DME Info
• Gene Name: PDE5A

1 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Molsidomine	DM9MA8O	Angina pectoris	BA40	Approved	[33]

References

• [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.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Anti-platelet therapy: phosphodiesterase inhibitors.Br J Clin Pharmacol.2011 Oct;72(4):634-46.
• [4] Effects of icariin on cGMP-specific PDE5 and cAMP-specific PDE4 activities. Asian J Androl. 2003 Mar;5(1):15-8.
• [5] 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.
• [6] Pulmonary arterial hypertension: the most devastating vascular complication of systemic sclerosis. Rheumatology (Oxford). 2009 Jun;48 Suppl 3:iii25-31.
• [7] 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.
• [8] 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.
• [9] Potent inhibition of human phosphodiesterase-5 by icariin derivatives. J Nat Prod. 2008 Sep;71(9):1513-7.
• [10] 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.
• [11] 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.
• [12] Inhibition of cyclic nucleotide phosphodiesterase by derivatives of 1,3-bis(cyclopropylmethyl)xanthine. J Med Chem. 1994 Feb 18;37(4):476-85.
• [13] 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.
• [14] WO patent application no. 2006,0180,88, Use of a pde 5 inhibitor for treating and preventing hypopigmentary disorders.
• [15] 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.
• [16] Pfizer. Product Development Pipeline. March 31 2009.
• [17] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014897)
• [18] 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.
• [19] Analogue-based Drug Discovery II. Janos Fischer,C. Robin Ganellin. Page(150).
• [20] Inhibition of cyclic adenosine-3',5'-monophosphate phosphodiesterase from vascular smooth muscle by rolipram analogues. J Med Chem. 1989 Jul;32(7):1450-7.
• [21] 4-(3-Chloro-4-methoxybenzyl)aminophthalazines: synthesis and inhibitory activity toward phosphodiesterase 5. J Med Chem. 2000 Jun 29;43(13):2523-9.
• [22] 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. (Target id: 1304).
• [23] 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.
• [24] 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.
• [25] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [26] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [27] A prenylated flavonol, sophoflavescenol: a potent and selective inhibitor of cGMP phosphodiesterase 5. Bioorg Med Chem Lett. 2002 Sep 2;12(17):2313-6.
• [28] Lorneic acids, trialkyl-substituted aromatic acids from a marine-derived actinomycete. J Nat Prod. 2009 Nov;72(11):2046-8.
• [29] DOI: 10.1021/op060099f
• [30] 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).
• [31] 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.
• [32] 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.
• [33] DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. (id: DB09282)