Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTZCG4L)

• DTT Name: Phosphodiesterase 3 (PDE3)
• Synonyms: Phosphodiesterase III; PDE3; Cyclic GMP inhibited phosphodiesterase; Cyclic AMP phosphodiesterase III; CGI-PDE; CAMP phosphodiesterase III
• Gene Name: NO-GeName
• DTT Type: Successful target; [1]
• Related Disease:
  Arterial occlusive disease [ICD-11: BD40]
  Cardiovascular disease [ICD-11: BA00-BE2Z]
  Castlemans disease [ICD-11: 4B2Y]
  Cough [ICD-11: MD12]
  Heart failure [ICD-11: BD10-BD1Z]
• BioChemical Class: Phosphoric diester hydrolase
• UniProt ID: NOUNIPROTAC
• TTD ID: T33754

Molecular Interaction Atlas (MIA) of This DTT

7 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cilostazol	DMZMSCT	Intermittent claudication	BD40.00	Approved	[2]
Enoximone	DMQVZJD	Congestive heart failure	BD10	Approved	[3]
Ibudilast	DM4LSPN	Castleman's disease	4B2Y	Approved	[4]
Inamrinone Lactate	DMRMFP4	Cardiac disease	BA00-BE2Z	Approved	[1]
Milrinone	DM8TUPF	Congestive heart failure	BD10	Approved	[2]
Olprinone	DMWBQKU	Heart failure	BD10-BD13	Approved	[5]
Oxtriphylline	DMLHSE3	Cough	MD12	Approved	[2]

7 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
K-134	DMD4OK0	Arteriosclerosis	BD40	Phase 2	[6], [7]
Org-30029	DMDZ4R2	Heart failure	BD10-BD13	Phase 2	[8], [9]
RPL-554	DMLD4VQ	Allergic rhinitis	CA08.0	Phase 2	[10]
Tipelukast	DMS9BDQ	Asthma	CA23	Phase 2	[11]
Tofisopam	DMTGNWU	Hyperuricaemia	5C55.Y	Phase 2	[12]
349U85.HCL	DMDFA3E	Cardiovascular disease	BA00-BE2Z	Phase 1	[13]
SDZ-MKS-492	DML6QJN	Asthma	CA23	Phase 1	[14], [15]

13 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
NSP-805	DMH2QBM	Heart failure	BD10-BD13	Discontinued in Phase 2	[16], [16]
OPC-8490	DM9ORUL	Cardiovascular disease	BA00-BE2Z	Discontinued in Phase 2	[17]
Org-9731	DMZEV63	Heart failure	BD10-BD13	Discontinued in Phase 2	[18], [19]
Pumafentrine	DMI8T41	Asthma	CA23	Discontinued in Phase 2	[20]
Tolafentrine	DMEROU4	Chronic obstructive pulmonary disease	CA22	Discontinued in Phase 2	[21]
NIP-520	DMMT7BC	Asthma	CA23	Discontinued in Phase 1	[22]
R 80122	DMU93JL	Cardiovascular disease	BA00-BE2Z	Discontinued in Phase 1	[23], [24]
Benafentrine dimaleate	DMXH3A2	Sepsis	1G40-1G41	Terminated	[25]
Org-9935	DMRZCH4	Asthma	CA23	Terminated	[26]
SDZ-ISQ-844	DMSZJUM	Asthma	CA23	Terminated	[27], [28]
Siguazodan	DM98K76	Allergy	4A80-4A85	Terminated	[29]
UD-CG-212	DM9FT5E	Heart failure	BD10-BD13	Terminated	[30], [31]
ZARDAVERINE	DMC38FO	Chronic obstructive pulmonary disease	CA22	Terminated	[32]

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cilostamide	DMBVIKY	Discovery agent	N.A.	Investigative	[33]

References

• [1] Effects of amrinone on hepatic ischemia-reperfusion injury in rats. J Hepatol. 2002 Jul;37(1):31-8.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [3] In vitro and in vivo effects of the phosphodiesterase-III inhibitor enoximone on malignant hyperthermia-susceptible swine. Anesthesiology. 2003 Apr;98(4):944-9.
• [4] Therapeutic targeting of 3',5'-cyclic nucleotide phosphodiesterases: inhibition and beyond. Nat Rev Drug Discov. 2019 Oct;18(10):770-796.
• [5] Olprinone: a phosphodiesterase III inhibitor with positive inotropic and vasodilator effects. Cardiovasc Drug Rev. 2002 Fall;20(3):163-74.
• [6] A phase II dose-ranging study of the phosphodiesterase inhibitor K-134 in patients with peripheral artery disease and claudication. J Vasc Surg. 2012 Feb;55(2):381-389.e1.
• [7] K-134, a Phosphodiesterase 3 Inhibitor, Prevents Brain Damage by Inhibiting Thrombus Formation in a Rat Cerebral Infarction Model. PLoS One. 2012; 7(10): e46432.
• [8] Effects of the positive inotropic agent Org 30029 on developed force and aequorin light transients in intact canine ventricular myocardium. Circ Res. 1993 Mar;72(3):597-606.
• [9] The presence of five cyclic nucleotide phosphodiesterase isoenzyme activities in bovine tracheal smooth muscle and the functional effects of select... Br J Pharmacol. 1991 Oct;104(2):471-7.
• [10] Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials.Lancet Respir Med.2013 Nov;1(9):714-27.
• [11] Company report (MediciNova)
• [12] The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis. J Neural Transm (Vienna). 2010 Nov;117(11):1319-25.
• [13] Pharmacokinetics and pharmacodynamics of a new cardiotonic vasodilator agent, 349U85, in normal subjects. Clin Pharmacol Ther. 1994 Jan;55(1):55-63.
• [14] Effects of a cyclic nucleotide phosphodiesterase isoenzyme type III inhibitor, SDZ MKS 492 on airway responsiveness in beagles. Arerugi. 1993 Aug;42(8):920-5.
• [15] Effects of MKS-492 on antigen-induced bronchoconstriction and allergic reaction in guinea pigs and rats. Jpn J Pharmacol. 1993 Dec;63(4):405-13.
• [16] [The effect of phosphodiesterase type 3 inhibitor on chorio-retinal blood flow in rabbits eyes].Nippon Ganka Gakkai Zasshi.2002 Oct;106(10):615-20.
• [17] Mechanism of action of OPC-8490 in human ventricular myocardium. Circulation. 1996 Feb 15;93(4):817-25.
• [18] Effects of a novel cardiotonic agent, Org 9731, on force and aequorin light transients in intact ventricular myocardium of the dog: involvement of ... J Card Fail. 1995 Mar;1(2):143-53.
• [19] The effects of various drugs on the myocardial inotropic response. Gen Pharmacol. 1995 Jan;26(1):1-31.
• [20] The selective phosphodiesterase 4 inhibitor roflumilast and phosphodiesterase 3/4 inhibitor pumafentrine reduce clinical score and TNF expression in experimental colitis in mice.PLoS One.2013;8(2):e56867.
• [21] Inhaled tolafentrine reverses pulmonary vascular remodeling via inhibition of smooth muscle cell migration
• [22] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [23] Inhibition of human cardiac cyclic AMP-phosphodiesterases by R 80122, a new selective cyclic AMP-phosphodiesterase III inhibitor: a comparison with other cardiotonic compounds. J Pharmacol Exp Ther. 1992 Oct;263(1):6-14.
• [24] Hemodynamic effects of the novel selective cAMP-phosphodiesterase III inhibitor R 80122 in anesthetized patients with moderate left ventricular dys... J Cardiothorac Vasc Anesth. 1995 Jun;9(3):272-7.
• [25] Studies on anti-allergic action of AH 21-132, a novel isozyme-selective phosphodiesterase inhibitor in airways. Jpn J Pharmacol. 1995 Feb;67(2):149-56.
• [26] The phosphodiesterase 3 inhibitor ORG 9935 inhibits oocyte maturation in the naturally selected dominant follicle in rhesus macaques.Contraception.2008 Apr;77(4):303-7.
• [27] [Effects of SDZ ISQ 844, a cyclic nucleotide phosphodiesterase isozyme type III/IV inhibitor, on the release of histamine from human peripheral leukocytes].Arerugi.1997 May;46(5):426-32.
• [28] Effects of inhaled SDZ ISQ 844, a cyclic nucleotide phosphodiesterase isoenzyme type III/IV inhibitor, on airway responsiveness in beagles. Arerugi. 1994 Apr;43(4):551-6.
• [29] Cyclic-AMP-dependent proliferation of a human osteoblast cell line (HOS cells) induced by hydroxyapatite: effect of exogenous nitric oxide. Acta Biomed. 2008 Aug;79(2):110-6.
• [30] Phosphodiesterase inhibition in ventricular cardiomyocytes from guinea-pig hearts. Br J Pharmacol. 1992 Sep;107(1):127-33.
• [31] Contribution of cAMP-phosphodiesterase inhibition and sensitization of the contractile proteins for calcium to the inotropic effect of pimobendan i... Circ Res. 1991 Mar;68(3):689-701.
• [32] Zardaverine: a cyclic AMP specific PDE III/IV inhibitor.Agents Actions Suppl.1991;34:379-402.
• [33] Phosphodiesterase 3 as a potential target for therapy of malignant tumors in the submandibular gland. Anticancer Drugs. 2001 Jan;12(1):79-83.