Target Information

Target General Infomation
Target ID
T02001
Former ID
TTDS00499
Target Name
Type IV phosphodiesterase
Gene Name
PDE4D
Synonyms
DPDE3; PDE43; PDE4D
Target Type
Clinical Trial
Disease Asthma; Chronic obstructive pulmonary disease [ICD9: 490-492, 493, 494-496; ICD10: J40-J44, J47, J45]
Atopic dermatitis [ICD9: 691.8, 692.9; ICD10: L00-L99]
Allergy [ICD9: 995.3; ICD10: T78.4]
Asthma [ICD10: J45]
Chronic obstructive pulmonary disease [ICD9: 490-492, 494-496; ICD10: J40-J44, J47]
Cognitive disorders [ICD9: 290-294, 294.0, 780.09, 780.9, 780.93; ICD10: F01-F07, F04, F05, R41.3]
Cutaneous T-cell lymphoma [ICD9: 202.1, 202.2; ICD10: C84.0, C84.1]
Chronic lymphocytic leukaemia [ICD10: C91]
Crohn's disease [ICD9: 555; ICD10: K50]
Glomerulonephritis [ICD9: 580-582; ICD10: N00, N01, N03, N18]
Huntington's disease [ICD9: 294.1, 333.4; ICD10: F02.2, G10]
Inflammatory disease [ICD9: 140-229, 147, 173, 573.3, 710-719; ICD10: C11, C44, K75.9, M00-M25]
Lung inflammation [ICD10: D86]
Mood disorder [ICD10: F30-F39]
Multiple scierosis [ICD9: 340; ICD10: G35]
Psoriasis [ICD9: 696; ICD10: L40]
Peripheral vascular disease [ICD9: 443.9; ICD10: I73.9]
Parkinson's disease [ICD9: 332; ICD10: G20]
Rhinitis [ICD9: 472.0, 477; ICD10: J00, J30, J31.0]
Rheumatoid arthritis [ICD9: 710-719, 714; ICD10: M05-M06]
Respiratory tract inflammation [ICD10: J00-J99]
Xerophthalmia [ICD10: E50.6-E50.7]
Function
Regulates the levels of camp inthe cell.
BioChemical Class
Phosphoric diester hydrolases
Target Validation
T02001
UniProt ID
Q08499
EC Number
EC 3.1.4.17
Sequence
MEAEGSSAPARAGSGEGSDSAGGATLKAPKHLWRHEQHHQYPLRQPQFRLLHPHHHLPPP
PPPSPQPQPQCPLQPPPPPPLPPPPPPPGAARGRYASSGATGRVRHRGYSDTERYLYCRA
MDRTSYAVETGHRPGLKKSRMSWPSSFQGLRRFDVDNGTSAGRSPLDPMTSPGSGLILQA
NFVHSQRRESFLYRSDSDYDLSPKSMSRNSSIASDIHGDDLIVTPFAQVLASLRTVRNNF
AALTNLQDRAPSKRSPMCNQPSINKATITEEAYQKLASETLEELDWCLDQLETLQTRHSV
SEMASNKFKRMLNRELTHLSEMSRSGNQVSEFISNTFLDKQHEVEIPSPTQKEKEKKKRP
MSQISGVKKLMHSSSLTNSSIPRFGVKTEQEDVLAKELEDVNKWGLHVFRIAELSGNRPL
TVIMHTIFQERDLLKTFKIPVDTLITYLMTLEDHYHADVAYHNNIHAADVVQSTHVLLST
PALEAVFTDLEILAAIFASAIHDVDHPGVSNQFLINTNSELALMYNDSSVLENHHLAVGF
KLLQEENCDIFQNLTKKQRQSLRKMVIDIVLATDMSKHMNLLADLKTMVETKKVTSSGVL
LLDNYSDRIQVLQNMVHCADLSNPTKPLQLYRQWTDRIMEEFFRQGDRERERGMEISPMC
DKHNASVEKSQVGFIDYIVHPLWETWADLVHPDAQDILDTLEDNREWYQSTIPQSPSPAP
DDPEEGRQGQTEKFQFELTLEEDGESDTEKDSGSQVEEDTSCSDSKTLCTQDSESTEIPL
DEQVEEEAVGEEEESQPEACVIDDRSPDT
Drugs and Mode of Action
Drug(s) DENBUFYLLINE Drug Info Phase 3 Cognitive disorders [525628]
SOTB07 Drug Info Phase 3 Asthma [524380]
AN-2898 Drug Info Phase 2 Atopic dermatitis [523369]
AWD-12-281 Drug Info Phase 2 Rhinitis [521859]
CC-1088 Drug Info Phase 2 Crohn's disease [521533]
GPD-1116 Drug Info Phase 2 Asthma [529143]
HT-0712 Drug Info Phase 2 Cognitive disorders [547671]
LIRIMILAST Drug Info Phase 2 Chronic obstructive pulmonary disease [551720]
MK-0873 Drug Info Phase 2 Psoriasis [521664]
Oglemilast Drug Info Phase 2 Asthma [522312]
OX-914 Drug Info Phase 2 Asthma [522443]
Piclamilast Drug Info Phase 2 Rheumatoid arthritis [525937]
Revamilast Drug Info Phase 2 Asthma [523630]
ROLIPRAM Drug Info Phase 2 Discovery agent [521483], [540724]
TA-7906 Drug Info Phase 2 Atopic dermatitis [548322]
TOFIMILAST Drug Info Phase 2 Chronic obstructive pulmonary disease [521675]
AVE-8112 Drug Info Phase 1 Parkinson's disease [524229]
GSK-356278 Drug Info Phase 1 Huntington's disease [522890]
MEM-1414 Drug Info Phase 1 Mood disorder [551843]
Ronomilast Drug Info Phase 1 Chronic obstructive pulmonary disease [547206]
CDP840 Drug Info Discontinued in Phase 2 Chronic obstructive pulmonary disease [545388]
CI-1018 Drug Info Discontinued in Phase 2 Asthma [546735]
Daxalipram Drug Info Discontinued in Phase 2 Multiple scierosis [547377]
KW-4490 Drug Info Discontinued in Phase 2 Asthma [547542]
LAS-37779 Drug Info Discontinued in Phase 2 Psoriasis [548191]
V-11294A Drug Info Discontinued in Phase 2 Asthma [547058]
D-4418 Drug Info Discontinued in Phase 1 Cutaneous T-cell lymphoma [546370]
SCH-351591 Drug Info Discontinued in Phase 1 Chronic obstructive pulmonary disease [546885]
YM-976 Drug Info Discontinued in Phase 1 Asthma [540755], [546870]
D-22888 Drug Info Terminated Allergy [546267]
GW-3600 Drug Info Terminated Asthma [546122]
NIK-616 Drug Info Terminated Asthma; Chronic obstructive pulmonary disease [547892]
TJN-598 Drug Info Terminated Glomerulonephritis [531152]
Torbafylline Drug Info Terminated Peripheral vascular disease [532864]
ZAPRINAST Drug Info Terminated Discovery agent [539935], [544527]
Inhibitor 1-(3,4-DIMETHOXYBENZYL)-6,7-DIMETHOXYISOQUINOLINE Drug Info [551374]
1-Butyl-3-methyl-3,7-dihydro-purine-2,6-dione Drug Info [526756]
1-Methyl-3-propyl-3,7-dihydro-purine-2,6-dione Drug Info [526756]
3-Isobutyl-1-methyl-3,9-dihydro-purine-2,6-dione Drug Info [533395]
3-ISOBUTYL-1-METHYLXANTHINE Drug Info [551374]
AN-2898 Drug Info [532329]
ASP-3258 Drug Info [543406]
AVE-8112 Drug Info [544367]
AWD-12-281 Drug Info [527926]
CC-1088 Drug Info [534801]
CD-160130 Drug Info [543406]
CDP840 Drug Info [527742]
CHF-5480 Drug Info [543406]
CI-1018 Drug Info [527082]
D-4418 Drug Info [529616]
Daxalipram Drug Info [532832]
DENBUFYLLINE Drug Info [526336]
GPD-1116 Drug Info [529143]
GSK-356278 Drug Info [532759]
GW-3600 Drug Info [534617]
HT-0712 Drug Info [543406]
KF-66490 Drug Info [529747]
KW-4490 Drug Info [529433]
L-454560 Drug Info [531102]
L-869298 Drug Info [528081]
LAS-37779 Drug Info [548192]
LIRIMILAST Drug Info [551871]
MEM-1414 Drug Info [533010]
MK-0873 Drug Info [529356]
NIK-616 Drug Info [550628]
OCID-2987 Drug Info [543406]
Oglemilast Drug Info [544060]
OX-914 Drug Info [549827]
PDE4 inhibitors Drug Info [543406]
PDE4 inhibitors Drug Info [543406]
Piclamilast Drug Info [551373]
Revamilast Drug Info [550161]
ROLIPRAM Drug Info [530753]
Ronomilast Drug Info [550312]
RS-25344 Drug Info [534698]
SCH-351591 Drug Info [526350]
SOTB07 Drug Info [543406]
TA-7906 Drug Info [526360]
TAS-203 Drug Info [543406]
TJN-598 Drug Info [531152]
TOFIMILAST Drug Info [551871]
UCB-101333-3 Drug Info [527990]
V-11294A Drug Info [526464]
YM-976 Drug Info [551871]
ZAPRINAST Drug Info [527441]
Modulator AL-59640 Drug Info [543406]
CH-3697 Drug Info [543406]
D-22888 Drug Info [534736]
Torbafylline Drug Info [532864]
ZL-N-91 Drug Info [543406]
Pathways
KEGG Pathway Purine metabolism
cAMP signaling pathway
Morphine addiction
PathWhiz Pathway Purine Metabolism
Reactome DARPP-32 events
G alpha (s) signalling events
WikiPathways G Protein Signaling Pathways
Myometrial Relaxation and Contraction Pathways
TSH signaling pathway
References
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Ref 521533ClinicalTrials.gov (NCT00045786) Study to Determine the Safety and Preliminary Efficacy of CC-1088 in the Treatment of Myelodysplastic Syndromes. U.S. National Institutes of Health.
Ref 521664ClinicalTrials.gov (NCT00132730) An Investigational Drug Study In Patients With COPD (Chronic Obstructive Pulmonary Disease) (MK-0873-005). U.S. National Institutes of Health.
Ref 521675ClinicalTrials.gov (NCT00150397) A Study of the Safety and Efficacy of Tofimilast in Adult Asthmatics. U.S. National Institutes of Health.
Ref 521859ClinicalTrials.gov (NCT00354510) Topical GW842470X In Adults Patients With Moderate Atopic Dermatitis. U.S. National Institutes of Health.
Ref 522312ClinicalTrials.gov (NCT00671073) Study To Assess Efficacy and Safety of Oglemilast in Patients With Chronic Obstructive Pulmonary Disease (COPD). U.S. National Institutes of Health.
Ref 522443ClinicalTrials.gov (NCT00758446) Efficacy and Safety Study of BLX-028914 in Subjects With Allergic Rhinitis. U.S. National Institutes of Health.
Ref 522890ClinicalTrials.gov (NCT01031186) First Time in Human Study. U.S. National Institutes of Health.
Ref 523369ClinicalTrials.gov (NCT01301508) Efficacy and Safety of AN2898 and AN2728 Topical Ointments to Treat Mild-to-Moderate Atopic Dermatitis. U.S. National Institutes of Health.
Ref 523630ClinicalTrials.gov (NCT01436890) A Clinical Trial to Study the Effects of Revamilast in Patients With Chronic Persistent Asthma. U.S. National Institutes of Health.
Ref 524229ClinicalTrials.gov (NCT01803945) A Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AVE8112 in Patients With Parkinson's Disease. U.S. National Institutes of Health.
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Ref 525628Denbufylline in dementia: a double-blind controlled study. Dement Geriatr Cogn Disord. 1999 Nov-Dec;10(6):505-10.
Ref 525937Effect of food and gender on the pharmacokinetics of RP 73401, a phosphodiesterase IV inhibitor. Int J Clin Pharmacol Ther. 2000 Dec;38(12):588-94.
Ref 529143Phosphodiesterase 4 inhibitor GPD-1116 markedly attenuates the development of cigarette smoke-induced emphysema in senescence-accelerated mice P1 strain. Am J Physiol Lung Cell Mol Physiol. 2008 Feb;294(2):L196-204. Epub 2007 Nov 9.
Ref 531152Effects 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.
Ref 532864Phosphodiesterase (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.
Ref 539935(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: 2919).
Ref 540724(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: 5260).
Ref 540755(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: 5292).
Ref 544527Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000060)
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Ref 551843The Quest for Human Longevity, Lewis D. Solo. Page(145).
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Ref 526350Bioorg Med Chem Lett. 2002 Jun 17;12(12):1621-3.Synthesis and profile of SCH351591, a novel PDE4 inhibitor.
Ref 526360Potential role of phosphodiesterase 7 in human T cell function: comparative effects of two phosphodiesterase inhibitors. Clin Exp Immunol. 2002 Jun;128(3):460-6.
Ref 526464Pharmacokinetic 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.
Ref 526756J Med Chem. 1992 Oct 30;35(22):4039-44.Effects of alkyl substitutions of xanthine skeleton on bronchodilation.
Ref 527082Bioorg Med Chem Lett. 2004 Jun 21;14(12):3303-6.New substituted triaza-benzo[cd]azulen-9-ones as promising phosphodiesterase-4 inhibitors.
Ref 527441J Med Chem. 2005 Feb 24;48(4):1237-43.8-Substituted analogues of 3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-adenine: highly potent and selective PDE4 inhibitors.
Ref 527742Bioorg Med Chem Lett. 2005 Dec 1;15(23):5241-6. Epub 2005 Sep 15.Discovery of a substituted 8-arylquinoline series of PDE4 inhibitors: structure-activity relationship, optimization, and identification of a highly potent, well tolerated, PDE4 inhibitor.
Ref 527926The 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.
Ref 527990Bioorg Med Chem Lett. 2006 Apr 1;16(7):1834-9. Epub 2006 Jan 24.First dual M3 antagonists-PDE4 inhibitors: synthesis and SAR of 4,6-diaminopyrimidine derivatives.
Ref 528081J Med Chem. 2006 Mar 23;49(6):1867-73.Enantiomer discrimination illustrated by the high resolution crystal structures of type 4 phosphodiesterase.
Ref 529143Phosphodiesterase 4 inhibitor GPD-1116 markedly attenuates the development of cigarette smoke-induced emphysema in senescence-accelerated mice P1 strain. Am J Physiol Lung Cell Mol Physiol. 2008 Feb;294(2):L196-204. Epub 2007 Nov 9.
Ref 529356MK-0873, a PDE4 inhibitor, does not influence the pharmacokinetics of theophylline in healthy male volunteers. Pulm Pharmacol Ther. 2008;21(3):573-7.
Ref 529433Pharmacokinetics 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.
Ref 529616Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking. Br J Pharmacol. 2008 Oct;155(3):288-90.
Ref 529747Effect of orally administered KF66490, a phosphodiesterase 4 inhibitor, on dermatitis in mouse models. Int Immunopharmacol. 2009 Jan;9(1):55-62.
Ref 530753Bioorg Med Chem. 2010 Mar 15;18(6):2204-18. Epub 2010 Feb 8.In silico search for multi-target anti-inflammatories in Chinese herbs and formulas.
Ref 531102Bioorg Med Chem Lett. 2010 Sep 15;20(18):5502-5. Epub 2010 Jul 21.The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors.
Ref 531152Effects 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.
Ref 532329An assessment of the genetic toxicology of novel boron-containing therapeutic agents. Environ Mol Mutagen. 2013 Jun;54(5):338-46.
Ref 532759GSK356278, 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.
Ref 532832Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in C57BL/6J mice. Front Neurosci. 2014 May 27;8:129.
Ref 532864Phosphodiesterase (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.
Ref 533010The 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.
Ref 533395J Med Chem. 1985 May;28(5):537-45.A new generation of phosphodiesterase inhibitors: multiple molecular forms of phosphodiesterase and the potential for drug selectivity.
Ref 534617Dual 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.
Ref 534698Comparison of recombinant human PDE4 isoforms: interaction with substrate and inhibitors. Cell Signal. 1998 Jun;10(6):427-40.
Ref 534736Effects 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.
Ref 534801Bioorg Med Chem Lett. 1998 Oct 6;8(19):2669-74.Thalidomide analogs and PDE4 inhibition.
Ref 543406(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).
Ref 544060Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking?. Br J Pharmacol. 2008 October; 155(3): 288-290.
Ref 544367Therapy for Parkinson's Disease: What is in the Pipeline?. Neurotherapeutics. 2014 January; 11(1): 24-33.
Ref 548192Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022894)
Ref 549827Orexo announces Phase IIa data on OX914 in rhinitis. Orexo. 24th March, 2009.
Ref 550161WO patent application no. 2012,1109,46, Pharmaceutical composition comprising the pde4 enzyme inhibitor revamilast and a disease modifying agent, preferably methotrexate .
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Ref 550628Preclinical trials in Chronic obstructive pulmonary disease in Japan (PO). 2004
Ref 551373Effects of piclamilast, a selective phosphodiesterase-4 inhibitor, on oxidative burst of sputum cells from mild asthmatics and stable <span class="caps">COPD</span> patients. Lung. 2004;182(6):369-77.
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Ref 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

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