Details of the Drug-Related molecule(s) Interaction Atlas

General Information of DTT (ID: TTZ97H5)

• DTT Name: Phosphodiesterase 4A (PDE4A) DTT Info
• Gene Name: PDE4A

Molecule-Related Drug & Molecule List

2 Approved Drug(s) Transported by This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dyphylline	DM8DZC1	Acute bronchial asthma	CA23	Approved	[1]
Enprofylline	DMFYZKN	Asthma	CA23	Approved	[2]

20 Clinical Trial Drug(s) Transported by This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
DENBUFYLLINE	DM2R15Q	Cognitive impairment	6D71	Phase 3	[3]
SOTB07	DMIG4OX	Asthma	CA23	Phase 3	[4]
AN-2898	DMDK7CL	Atopic dermatitis	EA80	Phase 2	[5]
AWD-12-281	DMVADGZ	Rhinitis	FA20	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	[4]
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	[9]
OX-914	DM5Q9RY	Asthma	CA23	Phase 2	[11]
Piclamilast	DMYL7VR	Rheumatoid arthritis	FA20	Phase 2	[12]
Revamilast	DM1FS2W	Asthma	CA23	Phase 2	[13]
TA-7906	DMZTAJL	Atopic dermatitis	EA80	Phase 2	[14]
TOFIMILAST	DMLCUAS	Chronic obstructive pulmonary disease	CA22	Phase 2	[15]
Tofisopam	DMTGNWU	Hyperuricaemia	5C55.Y	Phase 2	[16]
AVE-8112	DMZNTHJ	Parkinson disease	8A00.0	Phase 1	[17]
GSK-356278	DMIEAMU	Huntington disease	8A01.10	Phase 1	[18]
MEM-1414	DMA1KQV	Mood disorder	6A60-6E23	Phase 1	[19]
Ronomilast	DM82KWY	Chronic obstructive pulmonary disease	CA22	Phase 1	[20]

16 Discontinued Drug(s) Transported by This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cilomilast	DMHSM7I	Bronchitis	CA20	Discontinued in Phase 3	[21]
CDP840	DMUPJW4	Chronic obstructive pulmonary disease	CA22	Discontinued in Phase 2	[22]
CI-1018	DM03XVA	Asthma	CA23	Discontinued in Phase 2	[23]
Daxalipram	DMXO9BQ	Multiple sclerosis	8A40	Discontinued in Phase 2	[24]
GSK256066	DMBYQJH	Asthma	CA23	Discontinued in Phase 2	[25]
KW-4490	DMSWDKX	Asthma	CA23	Discontinued in Phase 2	[26]
LAS-37779	DM9J6BX	Psoriasis vulgaris	EA90	Discontinued in Phase 2	[27]
V-11294A	DMEV1H5	Asthma	CA23	Discontinued in Phase 2	[28]
D-4418	DMUPEJK	Cutaneous T-cell lymphoma	2B01	Discontinued in Phase 1	[29]
SCH-351591	DMK40VO	Chronic obstructive pulmonary disease	CA22	Discontinued in Phase 1	[30]
YM-976	DMCDK6S	Asthma	CA23	Discontinued in Phase 1	[31]
D-22888	DM7FTCV	Allergy	4A80-4A85	Terminated	[32]
GW-3600	DMSZH0I	Asthma	CA23	Terminated	[33]
NIK-616	DM4U7XB	Chronic obstructive pulmonary disease	CA22	Terminated	[34]
TJN-598	DMKSPYI	Glomerulonephritis	5D00.Y	Terminated	[35]
Torbafylline	DMRBGI6	Peripheral vascular disease	BD4Z	Terminated	[36]

42 Investigative Drug(s) Transported by This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(2,5-Diphenyl-furan-3-yl)-phenyl-methanone	DM97GFB	Discovery agent	N.A.	Investigative	[37]
(R)-Rolipram	DM95Z4Q	Discovery agent	N.A.	Investigative	[38]
(S)-Rolipram	DM1SJZ3	Discovery agent	N.A.	Investigative	[38]
1-Butyl-3-methyl-3,7-dihydro-purine-2,6-dione	DM9GRN8	Discovery agent	N.A.	Investigative	[39]
1-Methyl-3-propyl-3,7-dihydro-purine-2,6-dione	DM90LWT	Discovery agent	N.A.	Investigative	[39]
2,5-Bis-(3,4-dimethoxy-phenyl)-furan	DMH6RDL	Discovery agent	N.A.	Investigative	[37]
2,5-Bis-(3-cyclopentyloxy-4-methoxy-phenyl)-furan	DM28GQS	Discovery agent	N.A.	Investigative	[37]
4-(2,5-Diphenyl-furan-3-yl)-morpholine	DMVYALJ	Discovery agent	N.A.	Investigative	[37]
6-Azido-8-(3-iodo-phenyl)-quinoline	DM8BNWH	Discovery agent	N.A.	Investigative	[40]
6-Imidazol-1-ylmethyl-8-phenyl-quinoline	DMBQ3HV	Discovery agent	N.A.	Investigative	[40]
8-(3-Azido-phenyl)-6-iodo-quinoline	DM9J2LT	Discovery agent	N.A.	Investigative	[40]
8-(3-Azido-phenyl)-6-pyridin-4-ylmethyl-quinoline	DMON7RZ	Discovery agent	N.A.	Investigative	[40]
8-(3-Nitro-phenyl)-6-phenyl-[1,7]naphthyridine	DMP6Z3R	Discovery agent	N.A.	Investigative	[41]
8-(3-Nitro-phenyl)-6-pyridin-4-ylmethyl-quinoline	DM0N68L	Discovery agent	N.A.	Investigative	[40]
AL-59640	DMPHTX0	Xerophthalmia	5B55.Y	Investigative	[4]
ASP-3258	DMZ9GQR	Respiratory tract inflammation	CA07	Investigative	[4]
Benzyl-(2-imidazol-1-yl-quinazolin-4-yl)-amine	DM6I5MU	Discovery agent	N.A.	Investigative	[42]
Benzyl-(2-phenyl-quinazolin-4-yl)-amine	DM3X50C	Discovery agent	N.A.	Investigative	[42]
Benzyl-(2-pyridin-3-yl-quinazolin-4-yl)-amine	DMYDGCI	Discovery agent	N.A.	Investigative	[42]
Benzyl-(2-pyridin-4-yl-quinazolin-4-yl)-amine	DMESVWC	Discovery agent	N.A.	Investigative	[42]
Benzyl-(2-thiophen-2-yl-quinazolin-4-yl)-amine	DMH318X	Discovery agent	N.A.	Investigative	[42]
CD-160130	DMT6M5E	Chronic lymphocytic leukaemia	2A82.0	Investigative	[4]
CH-3697	DM0RFTJ	Asthma	CA23	Investigative	[4]
CHF-5480	DM5T64L	Chronic obstructive pulmonary disease	CA22	Investigative	[4]
CI-1044	DMG5D6B	Discovery agent	N.A.	Investigative	[43]
isobutylmethylxanthine	DM46F5X	Discovery agent	N.A.	Investigative	[44]
KF-66490	DMOUW0A	Atopic dermatitis	EA80	Investigative	[45]
KURAIDIN	DMLDUJ1	Discovery agent	N.A.	Investigative	[46]
KURARINOL	DMRV5YE	Discovery agent	N.A.	Investigative	[46]
L-454560	DM0P4V6	Discovery agent	N.A.	Investigative	[47]
L-791943	DM5D892	Discovery agent	N.A.	Investigative	[48]
L-869298	DMKEDU6	Discovery agent	N.A.	Investigative	[49]
NIS-62949	DM1R0WC	Discovery agent	N.A.	Investigative	[50]
NITRAQUAZONE	DMVDM0Q	Discovery agent	N.A.	Investigative	[51]
OCID-2987	DM69O3S	Inflammation	1A00-CA43.1	Investigative	[4]
ROLIPRAM	DMJ03UM	Discovery agent	N.A.	Investigative	[52]
RS-14491	DMRW57G	Discovery agent	N.A.	Investigative	[53]
RS-25344	DM0W2IS	Discovery agent	N.A.	Investigative	[54]
SOPHOFLAVESCENOL	DM8Y1S7	Discovery agent	N.A.	Investigative	[46]
TAS-203	DM07FBL	Respiratory tract inflammation	CA07	Investigative	[4]
UCB-101333-3	DMHYORU	Discovery agent	N.A.	Investigative	[55]
ZL-N-91	DM1H865	Lung inflammation	CA40.Z	Investigative	[4]

References

• [1] Ocular hypotension induced by topical dopaminergic drugs and phosphodiesterase inhibitors. Eur J Pharmacol. 1994 Jun 2;258(1-2):85-94.
• [2] Effects of enprofylline, a new xanthine derivate, on human pregnant myometrium. Am J Obstet Gynecol. 1987 Apr;156(4):958-62.
• [3] Pyrazolopyrimidine-2,4-dione sulfonamides: novel and selective calcitonin inducers. J Med Chem. 2002 May 23;45(11):2342-5.
• [4] 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: 1300).
• [5] An assessment of the genetic toxicology of novel boron-containing therapeutic agents. Environ Mol Mutagen. 2013 Jun;54(5):338-46.
• [6] 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.
• [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] Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking . Br J Pharmacol. 2008 October; 155(3): 288-290.
• [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] Orexo announces Phase IIa data on OX914 in rhinitis. Orexo. 24th March, 2009.
• [12] 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.
• [13] WO patent application no. 2012,1109,46, Pharmaceutical composition comprising the pde4 enzyme inhibitor revamilast and a disease modifying agent, preferably methotrexate .
• [14] 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.
• [15] GSK256066, an exceptionally high-affinity and selective inhibitor of phosphodiesterase 4 suitable for administration by inhalation: in vitro, kinetic, and in vivo characterization. J Pharmacol Exp Ther. 2011 Apr;337(1):145-54.
• [16] 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.
• [17] Therapy for Parkinson's Disease: What is in the Pipeline . Neurotherapeutics. 2014 January; 11(1): 24-33.
• [18] 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.
• [19] 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.
• [20] Clinical pipeline report, company report or official report of Avarx.
• [21] Emerging drugs for asthma. Expert Opin Emerg Drugs. 2008 Dec;13(4):643-53.
• [22] 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.
• [23] New substituted triaza-benzo[cd]azulen-9-ones as promising phosphodiesterase-4 inhibitors. Bioorg Med Chem Lett. 2004 Jun 21;14(12):3303-6.
• [24] Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in C57BL/6J mice. Front Neurosci. 2014 May 27;8:129.
• [25] Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
• [26] 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.
• [27] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022894)
• [28] 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.
• [29] Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking. Br J Pharmacol. 2008 Oct;155(3):288-90.
• [30] Synthesis and profile of SCH351591, a novel PDE4 inhibitor. Bioorg Med Chem Lett. 2002 Jun 17;12(12):1621-3.
• [31] Antiasthmatic effect of YM976, a novel PDE4 inhibitor, in guinea pigs. J Pharmacol Exp Ther. 2001 Apr;297(1):165-73.
• [32] 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.
• [33] 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.
• [34] Preclinical trials in Chronic obstructive pulmonary disease in Japan (PO). 2004
• [35] 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.
• [36] 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.
• [37] Substituted furans as inhibitors of the PDE4 enzyme. Bioorg Med Chem Lett. 1999 Feb 8;9(3):323-6.
• [38] PDE4 inhibitors roflumilast and rolipram augment PGE2 inhibition of TGF-{beta}1-stimulated fibroblasts. Am J Physiol Lung Cell Mol Physiol. 2009 Jun;296(6):L959-69.
• [39] Effects of alkyl substitutions of xanthine skeleton on bronchodilation. J Med Chem. 1992 Oct 30;35(22):4039-44.
• [40] Hunting the emesis and efficacy targets of PDE4 inhibitors: identification of the photoaffinity probe 8-(3-azidophenyl)-6- [(4-iodo-1H-1-imidazolyl... J Med Chem. 2000 Oct 19;43(21):3820-3.
• [41] Palladium-catalyzed cross-coupling reactions for the synthesis of 6, 8-disubstituted 1,7-naphthyridines: a novel class of potent and selective phos... J Med Chem. 2000 Feb 24;43(4):675-82.
• [42] Discovery of potent cyclic GMP phosphodiesterase inhibitors. 2-Pyridyl- and 2-imidazolylquinazolines possessing cyclic GMP phosphodiesterase and th... J Med Chem. 1995 Sep 1;38(18):3547-57.
• [43] Synthesis, structure-activity relationships, and pharmacological profile of 9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6, 7,1-hi]indol... J Med Chem. 2000 Dec 14;43(25):4850-67.
• [44] A new generation of phosphodiesterase inhibitors: multiple molecular forms of phosphodiesterase and the potential for drug selectivity. J Med Chem. 1985 May;28(5):537-45.
• [45] Effect of orally administered KF66490, a phosphodiesterase 4 inhibitor, on dermatitis in mouse models. Int Immunopharmacol. 2009 Jan;9(1):55-62.
• [46] A prenylated flavonol, sophoflavescenol: a potent and selective inhibitor of cGMP phosphodiesterase 5. Bioorg Med Chem Lett. 2002 Sep 2;12(17):2313-6.
• [47] The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors. Bioorg Med Chem Lett. 2010 Sep 15;20(18):5502-5.
• [48] Discovery of L-791,943: a potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor. Bioorg Med Chem Lett. 2002 Jun 3;12(11):1457-61.
• [49] Enantiomer discrimination illustrated by the high resolution crystal structures of type 4 phosphodiesterase. J Med Chem. 2006 Mar 23;49(6):1867-73.
• [50] Pharmacology of a novel, orally active PDE4 inhibitor. Pharmacology. 2009;83(5):275-86.
• [51] Synthesis and biological evaluation of 2,5-dihydropyrazol. Bioorg Med Chem Lett. 2000 Dec 4;10(23):2661-4.
• [52] Discovery of micromolar PDE IV inhibitors that exhibit much reduced affinity for the [3H]rolipram binding site: 3-norbornyloxy-4-methoxyphenylmethylene oxindoles, Bioorg. Med. Chem. Lett. 5(17):1965-1968 (1995).
• [53] Novel heterocyclic-fused pyridazinones as potent and selective phosphodiesterase IV inhibitors. J Med Chem. 1997 May 9;40(10):1417-21.
• [54] Comparison of recombinant human PDE4 isoforms: interaction with substrate and inhibitors. Cell Signal. 1998 Jun;10(6):427-40.
• [55] 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.