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]
• Related Disease:
  Hypertension [ICD-11: BA00-BA04]
  Innate/adaptive immunodeficiency [ICD-11: 4A00]
  Sexual dysfunction [ICD-11: HA00-HA01]
  Tonus and reflex abnormality [ICD-11: MB47]
• 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.
• 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	Hypertension	BA00-BA04	Approved	[3]
Papaverine	DMCA9QP	Spasm	MB47.3	Approved	[4]
Rhucin	DM3ADGP	Erectile dysfunction	HA01.1	Approved	[5], [6], [7], [8]
Tadalafil	DMJZHT1	Erectile dysfunction	HA01.1	Approved	[9], [8], [10]
Udenafil	DM1IQRP	Erectile dysfunction	HA01.1	Approved	[11]
Vardenafil	DMTBGW8	Erectile dysfunction	HA01.1	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	[12]
ICARIIN	DMOJQGT	N. A.	N. A.	Phase 3	[13]
PF-489791	DM3C8GQ	Chronic obstructive pulmonary disease	CA22	Phase 2	[14]
UK-371800	DMI8795	Erectile dysfunction	HA01.1	Phase 1	[15]

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	[16]
DASANTAFIL	DMOWIGC	Erectile dysfunction	HA01.1	Discontinued in Phase 2	[2]
E-4021	DMWIA56	Cardiovascular disease	BA00-BE2Z	Discontinued in Phase 2	[17]
EMR-62203	DMIQRJW	Erectile dysfunction	HA01.1	Discontinued in Phase 2	[18]
SINITRODIL	DMMZ2JT	Angina pectoris	BA40	Discontinued in Phase 2	[2]
SLX-2101	DM1J0YB	Erectile dysfunction	HA01.1	Discontinued in Phase 2	[19]
UK-369003	DMHXRZF	Erectile dysfunction	HA01.1	Discontinued in Phase 1/2	[20], [21]
FR-229934	DMT6R8I	Erectile dysfunction	HA01.1	Terminated	[22]
IMAZODAN	DMWTFO3	N. A.	N. A.	Terminated	[23]
SKF-96231	DMS2M58	Asthma	CA23	Terminated	[24]
Trequinsin	DMQRSMD	N. A.	N. A.	Terminated	[25]
Zaprinast	DMGH3T5	N. A.	N. A.	Terminated	[26]

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	[13]
7-(2-Hydroxyethyl)-3-O-rhamnosylicariin	DMBIY98	Discovery agent	N.A.	Investigative	[13]
8-prenylapigenin	DM2VC0E	Discovery agent	N.A.	Investigative	[13]
8-prenylquercetin	DMZC1SV	Discovery agent	N.A.	Investigative	[13]
Aom-0890	DMT4I2W	Erectile dysfunction	HA01.1	Investigative	[27]
Benzo[1,3]dioxol-5-ylmethyl-quinazolin-4-yl-amine	DM067NL	Discovery agent	N.A.	Investigative	[28]
Cartazolate	DMSKT8G	Discovery agent	N.A.	Investigative	[29]
CKD-533	DMH204Y	Erectile dysfunction	HA01.1	Investigative	[27]
Gamma-Glutamyl[S-(2-Iodobenzyl)Cysteinyl]Glycine	DMHNJDE	Discovery agent	N.A.	Investigative	[30]
Guanosine-5'-Monophosphate	DM3SLZK	Discovery agent	N.A.	Investigative	[30]
Icariside II	DM3DB8X	Discovery agent	N.A.	Investigative	[13]
isobutylmethylxanthine	DM46F5X	Discovery agent	N.A.	Investigative	[31]
Kuraidin	DMLDUJ1	Discovery agent	N.A.	Investigative	[32]
KURARINOL	DMRV5YE	Discovery agent	N.A.	Investigative	[32]
LORNEIC ACID A	DM0ECUK	Discovery agent	N.A.	Investigative	[33]
ROLIPRAM	DMJ03UM	Discovery agent	N.A.	Investigative	[28]
RWJ-387273	DM28IKN	Discovery agent	N.A.	Investigative	[34]
SCH-57726	DMDK8TR	Discovery agent	N.A.	Investigative	[35]
SCH51866	DMCWSJP	Discovery agent	N.A.	Investigative	[36]
SOPHOFLAVESCENOL	DM8Y1S7	Discovery agent	N.A.	Investigative	[32]
SOPHORAFLAVANONE B	DMUVKX5	Discovery agent	N.A.	Investigative	[13]
T0156	DMZE9TW	Discovery agent	N.A.	Investigative	[37]
TPN-729	DMW9G7H	Erectile dysfunction	HA01.1	Investigative	[27]

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	[38]

References

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• [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] 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.
• [7] Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51.
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• [16] Inhibition of cyclic nucleotide phosphodiesterase by derivatives of 1,3-bis(cyclopropylmethyl)xanthine. J Med Chem. 1994 Feb 18;37(4):476-85.
• [17] 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.
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• [28] 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.
• [29] 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.
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• [31] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [32] A prenylated flavonol, sophoflavescenol: a potent and selective inhibitor of cGMP phosphodiesterase 5. Bioorg Med Chem Lett. 2002 Sep 2;12(17):2313-6.
• [33] Lorneic acids, trialkyl-substituted aromatic acids from a marine-derived actinomycete. J Nat Prod. 2009 Nov;72(11):2046-8.
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• [37] 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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