Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTSKMI8)

• DTT Name: Phosphodiesterase 4D (PDE4D)
• Synonyms: cAMP-specific 3',5'-cyclic phosphodiesterase 4D; PDE43; DPDE3
• Gene Name: PDE4D
• DTT Type: Successful target; [1]
• BioChemical Class: Phosphoric diester hydrolase
• UniProt ID: PDE4D_HUMAN
• TTD ID: T02001
• EC Number: EC 3.1.4.53
• Sequence:
  MEAEGSSAPARAGSGEGSDSAGGATLKAPKHLWRHEQHHQYPLRQPQFRLLHPHHHLPPP
  PPPSPQPQPQCPLQPPPPPPLPPPPPPPGAARGRYASSGATGRVRHRGYSDTERYLYCRA
  MDRTSYAVETGHRPGLKKSRMSWPSSFQGLRRFDVDNGTSAGRSPLDPMTSPGSGLILQA
  NFVHSQRRESFLYRSDSDYDLSPKSMSRNSSIASDIHGDDLIVTPFAQVLASLRTVRNNF
  AALTNLQDRAPSKRSPMCNQPSINKATITEEAYQKLASETLEELDWCLDQLETLQTRHSV
  SEMASNKFKRMLNRELTHLSEMSRSGNQVSEFISNTFLDKQHEVEIPSPTQKEKEKKKRP
  MSQISGVKKLMHSSSLTNSSIPRFGVKTEQEDVLAKELEDVNKWGLHVFRIAELSGNRPL
  TVIMHTIFQERDLLKTFKIPVDTLITYLMTLEDHYHADVAYHNNIHAADVVQSTHVLLST
  PALEAVFTDLEILAAIFASAIHDVDHPGVSNQFLINTNSELALMYNDSSVLENHHLAVGF
  KLLQEENCDIFQNLTKKQRQSLRKMVIDIVLATDMSKHMNLLADLKTMVETKKVTSSGVL
  LLDNYSDRIQVLQNMVHCADLSNPTKPLQLYRQWTDRIMEEFFRQGDRERERGMEISPMC
  DKHNASVEKSQVGFIDYIVHPLWETWADLVHPDAQDILDTLEDNREWYQSTIPQSPSPAP
  DDPEEGRQGQTEKFQFELTLEEDGESDTEKDSGSQVEEDTSCSDSKTLCTQDSESTEIPL
  DEQVEEEAVGEEEESQPEACVIDDRSPDT
• Function: Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  cAMP signaling pathway (hsa04024)
  Morphine addiction (hsa05032)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  DARPP-32 events (R-HSA-180024)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Papaverine	DMCA9QP	Brain ischaemia	8B1Z	Approved	[1]

20 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
DENBUFYLLINE	DM2R15Q	Cognitive impairment	6D71	Phase 3	[2]
SOTB07	DMIG4OX	Asthma	CA23	Phase 3	[3]
AN-2898	DMDK7CL	Atopic dermatitis	EA80	Phase 2	[4]
AWD-12-281	DMVADGZ	Rhinitis	FA20	Phase 2	[5]
BPN14770	DMWVPO0	Alzheimer disease	8A20	Phase 2	[6]
CC-1088	DMQ874W	Crohn disease	DD70	Phase 2	[7]
GPD-1116	DMOQ7YI	Asthma	CA23	Phase 2	[8]
HT-0712	DM2WP8F	Cognitive impairment	6D71	Phase 2	[3]
LIRIMILAST	DMD4KAU	Chronic obstructive pulmonary disease	CA22	Phase 2	[9]
MK-0873	DM0568C	Psoriasis vulgaris	EA90	Phase 2	[10]
Oglemilast	DMVC90W	Asthma	CA23	Phase 2	[11]
OX-914	DM5Q9RY	Asthma	CA23	Phase 2	[12]
Piclamilast	DMYL7VR	Rheumatoid arthritis	FA20	Phase 2	[13]
Revamilast	DM1FS2W	Asthma	CA23	Phase 2	[14]
TA-7906	DMZTAJL	Atopic dermatitis	EA80	Phase 2	[15]
TOFIMILAST	DMLCUAS	Chronic obstructive pulmonary disease	CA22	Phase 2	[9]
AVE-8112	DMZNTHJ	Parkinson disease	8A00.0	Phase 1	[16]
GSK-356278	DMIEAMU	Huntington disease	8A01.10	Phase 1	[17]
MEM-1414	DMA1KQV	Mood disorder	6A60-6E23	Phase 1	[18]
Ronomilast	DM82KWY	Chronic obstructive pulmonary disease	CA22	Phase 1	[19]

15 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CDP840	DMUPJW4	Chronic obstructive pulmonary disease	CA22	Discontinued in Phase 2	[20]
CI-1018	DM03XVA	Asthma	CA23	Discontinued in Phase 2	[21]
Daxalipram	DMXO9BQ	Multiple sclerosis	8A40	Discontinued in Phase 2	[22]
KW-4490	DMSWDKX	Asthma	CA23	Discontinued in Phase 2	[23]
LAS-37779	DM9J6BX	Psoriasis vulgaris	EA90	Discontinued in Phase 2	[24]
V-11294A	DMEV1H5	Asthma	CA23	Discontinued in Phase 2	[25]
D-4418	DMUPEJK	Cutaneous T-cell lymphoma	2B01	Discontinued in Phase 1	[26]
SCH-351591	DMK40VO	Chronic obstructive pulmonary disease	CA22	Discontinued in Phase 1	[27]
YM-976	DMCDK6S	Asthma	CA23	Discontinued in Phase 1	[9]
D-22888	DM7FTCV	Allergy	4A80-4A85	Terminated	[28]
GW-3600	DMSZH0I	Asthma	CA23	Terminated	[29]
NIK-616	DM4U7XB	Chronic obstructive pulmonary disease	CA22	Terminated	[30]
TJN-598	DMKSPYI	Glomerulonephritis	5D00.Y	Terminated	[31]
Torbafylline	DMRBGI6	Peripheral vascular disease	BD4Z	Terminated	[32]
ZAPRINAST	DMGH3T5	N. A.	N. A.	Terminated	[33]

17 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1-Butyl-3-methyl-3,7-dihydro-purine-2,6-dione	DM9GRN8	Discovery agent	N.A.	Investigative	[34]
1-Methyl-3-propyl-3,7-dihydro-purine-2,6-dione	DM90LWT	Discovery agent	N.A.	Investigative	[34]
AL-59640	DMPHTX0	Xerophthalmia	5B55.Y	Investigative	[3]
ASP-3258	DMZ9GQR	Respiratory tract inflammation	CA07	Investigative	[3]
CD-160130	DMT6M5E	Chronic lymphocytic leukaemia	2A82.0	Investigative	[3]
CH-3697	DM0RFTJ	Asthma	CA23	Investigative	[3]
CHF-5480	DM5T64L	Chronic obstructive pulmonary disease	CA22	Investigative	[3]
isobutylmethylxanthine	DM46F5X	Discovery agent	N.A.	Investigative	[1]
KF-66490	DMOUW0A	Atopic dermatitis	EA80	Investigative	[35]
L-454560	DM0P4V6	Discovery agent	N.A.	Investigative	[36]
L-869298	DMKEDU6	Discovery agent	N.A.	Investigative	[37]
OCID-2987	DM69O3S	Inflammation	1A00-CA43.1	Investigative	[3]
ROLIPRAM	DMJ03UM	Discovery agent	N.A.	Investigative	[38]
RS-25344	DM0W2IS	Discovery agent	N.A.	Investigative	[39]
TAS-203	DM07FBL	Respiratory tract inflammation	CA07	Investigative	[3]
UCB-101333-3	DMHYORU	Discovery agent	N.A.	Investigative	[40]
ZL-N-91	DM1H865	Lung inflammation	CA40.Z	Investigative	[3]

References

• [1] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [2] Pyrazolopyrimidine-2,4-dione sulfonamides: novel and selective calcitonin inducers. J Med Chem. 2002 May 23;45(11):2342-5.
• [3] 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: 1303).
• [4] An assessment of the genetic toxicology of novel boron-containing therapeutic agents. Environ Mol Mutagen. 2013 Jun;54(5):338-46.
• [5] The phosphodiesterase 4 inhibitor AWD 12-281 is active in a new guinea-pig model of allergic skin inflammation predictive of human skin penetration and suppresses both Th1 and Th2 cytokines in mice. J Pharm Pharmacol. 2005 Dec;57(12):1609-17.
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Thalidomide analogs and PDE4 inhibition. Bioorg Med Chem Lett. 1998 Oct 6;8(19):2669-74.
• [8] Phosphodiesterase 4 inhibitor GPD-1116 markedly attenuates the development of cigarette smoke-induced emphysema in senescence-accelerated mice P1 s... Am J Physiol Lung Cell Mol Physiol. 2008 Feb;294(2):L196-204.
• [9] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [10] MK-0873, a PDE4 inhibitor, does not influence the pharmacokinetics of theophylline in healthy male volunteers. Pulm Pharmacol Ther. 2008;21(3):573-7.
• [11] Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking . Br J Pharmacol. 2008 October; 155(3): 288-290.
• [12] Orexo announces Phase IIa data on OX914 in rhinitis. Orexo. 24th March, 2009.
• [13] Effects of piclamilast, a selective phosphodiesterase-4 inhibitor, on oxidative burst of sputum cells from mild asthmatics and stable COPD patients. Lung. 2004;182(6):369-77.
• [14] WO patent application no. 2012,1109,46, Pharmaceutical composition comprising the pde4 enzyme inhibitor revamilast and a disease modifying agent, preferably methotrexate .
• [15] Potential role of phosphodiesterase 7 in human T cell function: comparative effects of two phosphodiesterase inhibitors. Clin Exp Immunol. 2002 Jun;128(3):460-6.
• [16] Therapy for Parkinson's Disease: What is in the Pipeline . Neurotherapeutics. 2014 January; 11(1): 24-33.
• [17] GSK356278, a potent, selective, brain-penetrant phosphodiesterase 4 inhibitor that demonstrates anxiolytic and cognition-enhancing effects without inducing side effects in preclinical species. J Pharmacol Exp Ther. 2014 Jul;350(1):153-63.
• [18] The effect of the novel phosphodiesterase-4 inhibitor MEM 1414 on the allergen induced responses in mild asthma. BMC Pulm Med. 2014 Oct 28;14:166.
• [19] Clinical pipeline report, company report or official report of Avarx.
• [20] Discovery of a substituted 8-arylquinoline series of PDE4 inhibitors: structure-activity relationship, optimization, and identification of a highly... Bioorg Med Chem Lett. 2005 Dec 1;15(23):5241-6.
• [21] New substituted triaza-benzo[cd]azulen-9-ones as promising phosphodiesterase-4 inhibitors. Bioorg Med Chem Lett. 2004 Jun 21;14(12):3303-6.
• [22] Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in C57BL/6J mice. Front Neurosci. 2014 May 27;8:129.
• [23] Pharmacokinetics and metabolism of KW-4490, a selective phosphodiesterase 4 inhibitor: difference in excretion of KW-4490 and acylglucuronide metabolites between rats and cynomolgus monkeys. Xenobiotica. 2008 May;38(5):511-26.
• [24] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022894)
• [25] Pharmacokinetic and pharmacodynamic profile following oral administration of the phosphodiesterase (PDE)4 inhibitor V11294A in healthy volunteers. Br J Clin Pharmacol. 2002 Nov;54(5):478-84.
• [26] Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking. Br J Pharmacol. 2008 Oct;155(3):288-90.
• [27] Synthesis and profile of SCH351591, a novel PDE4 inhibitor. Bioorg Med Chem Lett. 2002 Jun 17;12(12):1621-3.
• [28] Effects of a selective PDE4 inhibitor, D-22888, on human airways and eosinophils in vitro and late phase allergic pulmonary eosinophilia in guinea pigs. Pulm Pharmacol Ther. 1998 Feb;11(1):13-21.
• [29] Dual inhibition of human type 4 phosphodiesterase isostates by (R, R)-(+/-)-methyl 3-acetyl-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-3- methyl-1-pyrrolidinecarboxylate. Biochemistry. 1998 May 12;37(19):6894-904.
• [30] Preclinical trials in Chronic obstructive pulmonary disease in Japan (PO). 2004
• [31] Effects of TJN-598, a new selective phosphodiesterase type IV inhibitor on anti-Thy1 nephritis in rats. Clin Exp Nephrol. 2011 Feb;15(1):14-24.
• [32] Phosphodiesterase (PDE) inhibitor torbafylline (HWA 448) attenuates burn-induced rat skeletal muscle proteolysis through the PDE4/cAMP/EPAC/PI3K/Akt pathway. Mol Cell Endocrinol. 2014 Aug 5;393(1-2):152-63.
• [33] 8-Substituted analogues of 3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-adenine: highly potent and selective PDE4 inhibitors. J Med Chem. 2005 Feb 24;48(4):1237-43.
• [34] Effects of alkyl substitutions of xanthine skeleton on bronchodilation. J Med Chem. 1992 Oct 30;35(22):4039-44.
• [35] Effect of orally administered KF66490, a phosphodiesterase 4 inhibitor, on dermatitis in mouse models. Int Immunopharmacol. 2009 Jan;9(1):55-62.
• [36] The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors. Bioorg Med Chem Lett. 2010 Sep 15;20(18):5502-5.
• [37] Enantiomer discrimination illustrated by the high resolution crystal structures of type 4 phosphodiesterase. J Med Chem. 2006 Mar 23;49(6):1867-73.
• [38] In silico search for multi-target anti-inflammatories in Chinese herbs and formulas. Bioorg Med Chem. 2010 Mar 15;18(6):2204-2218.
• [39] Comparison of recombinant human PDE4 isoforms: interaction with substrate and inhibitors. Cell Signal. 1998 Jun;10(6):427-40.
• [40] First dual M3 antagonists-PDE4 inhibitors: synthesis and SAR of 4,6-diaminopyrimidine derivatives. Bioorg Med Chem Lett. 2006 Apr 1;16(7):1834-9.