US EPA

7456671 

Journal Article 

Octahydrocyclopenta[c]pyridine and octahydrocyclopenta[c]pyran analogues as a protease activated receptor 1 (PAR1) antagonist 

Wadood, A; Kim, H; Park, CM; Song, JH; Lee, S 

2015 

Yes 

Archives of Pharmacal Research
ISSN: 0253-6269
EISSN: 1976-3786 

Pharmaceutical Society of Korea 

38 

11 

2029-2041 

English 

10.1007/s12272-015-0623-6 

Protease activated receptor 1 (PAR1) has been considered as a promising antiplatelet target to prevent thrombotic cardiovascular events in patients with prior myocardial infarction or peripheral arterial diseases. Previously, we found a series of octahydroindene analogues to have high potency on PAR1 and no significant cytotoxicity but poor metabolic stability in human and rat liver microsomes. We have designed and synthesized fused 6/5 heterobicycle analogues with octahydrocyclopenta[c]pyridine or octahydrocyclopenta[c]pyran core scaffold by the insertion of heteroatom at C5 of octahydroindene ring aiming to improvement of metabolic stability. Both heterobicycle analogues showed much more improved metabolic stability compared with octahydroindenes without remarkable decrease in activity. Compounds 22 (IC50 = 110 nM) and 33 (IC50 = 50 nM) from this series showed good activity on PAR1 with moderate metabolic stability. © 2015 The Pharmaceutical Society of Korea. 

6/5 Fused heterobicycle; Metabolic stability; Octahydrocyclopenta[c]pyran; Octahydrocyclopenta[c]pyridine; Octahydroindene; Protease activated receptor 1; 2 carbamoyl 5 2 [5 (3 fluorophenyl)pyridine 2 yl]vinyl] 6 methyloctahydro 2h cyclopenta[c]pyridine 6 yl carbamate; 5 2 [5 (3 fluorophenyl)pyridine 2 yl]vinyl] 2 formyl 6 methyloctahydro 2h cyclopenta[c]pyridine 6 yl carbamate; 5 2 [5 (3 fluorophenyl)pyridine 2 yl]vinyl] 5' oxooctahydro 3'h spiro(cyclopenta [c]pyidine 6,2' furan) 2(1h) carbaldhyde; 5 2 [5 (3 fluorophenyl)pyridine 2 yl]vinyl] 6 methyloctahydro 2h cyclopenta[c]pyridine 6 yl carbamate; 5 2 [5 (3 fluorophenyl)pyridine 2 yl]vinyl]decahydro 5'h spiro(cyclopenta [c]pyidine 6,2' furan) 5' one; ethyl 5 (tert butoxycarbonylamino)pent 2 enoate; octahydrocyclopenta[c]pyran derivative; octahydrocyclopenta[c]pyridine derivative; proteinase activated receptor 1; proteinase inhibitor; pyran derivative; pyridine derivative; tert butyl 5 (hydroxypent 3 enyl)carbamate; tert butyl 5 2 [5 (3 fluorophenyl)pyridine 2 yl]vinyl] 5' oxooctahydro 3'h spiro(cyclopenta [c]pyidine 6,2' furan) 2(1h) carboxylate; tert butyl 5 2 [5 (3 fluorophenyl)pyridine 2 yl]vinyl] 6 hydroxy 6 methyloctahydro 2h cyclopenta[c]pyridine 2 carboxylate; tert butyl 5 formyl 6 hydroxy 6 methyloctahydro 2h cyclopenta[c]pyridine 2 carboxylate; tert butyl 5 [[(tert butyldimethylsilyl)oxy]methyl] 5' oxooctahydro 3' h spiro(cyclopenta [c]pyidine 6,2' furan) 2(1h) carboxylate; tert butyl 5 [[(tert butyldimethylsilyl)oxy]methyl] 6 hydroxy 6 methyloctahydro 2h cyclopenta[c]pyridine 2 carboxylate; tert butyl 5 [[(tert butyldimethylsilyl)oxy]methyl] 6 hydroxy 9 (3 hydroxylpropyl)octahydro 2h cyclopenta[c]pyidine 2 carboxylate; tert butyl 5 [[(tert butyldimethylsilyl)oxy]methyl] 6 octahydro 2h cyclopental[c]pyridine 2 carboxylate; tert butyl 5 [[(tert butyldimethylsilyl)oxy]methyl] 6 oxo 1,3,4,4a,5,6 hexahydro 2h cyclopental[c]pyridine 2 carboxylate; tert butyl 6 (carbamoyloxy) 5 2 [5 (3 fluorophenyl)pyridine 2 yl]vinyl] 6 methyloctahydro 2h cyclopenta[c]pyridine 2 carboxylate; tert butyl 6 allyl 5 [[(tert butyldimethylsilyl)oxy]methyl] 6 hydroxyoctahydro 2h cyclopenta[c]pyidine 2 carboxylate; tert butyl 6 hydroxy 5 (hydroxymethyl) 6 methyloctahydro 2h cyclopenta[c]pyridine 2 carboxylate; tert butyl [5 [(tert butyldimethylsily)loxy]pent 3 en 1 yl](prop 2 yn 1 yl)carbamate; tert butyl [5 [(tert butyldimethylsilyl)oxy]pent 3 en 1 yl]carbamate; tert butyl(3 hydroxypropyl)carbamate; tert butyl(3 oxopropyl)carbamate; unclassified drug; proteinase activated receptor 1; pyran derivative; pyridine derivative; animal experiment; Article; biological activity; chemical analysis; clinical evaluation; comparative study; controlled study; cytotoxicity; drug potency; drug structure; human; liver microsome; metabolic stability; nonhuman; rat; thrombocyte membrane; animal; antagonists and inhibitors; chemistry; IC50; metabolism; structure activity relation; synthesis; Animals; Humans; Inhibitory Concentration 50; Microsomes, Liver; Pyrans; Pyridines; Rats; Receptor, PAR-1; Structure-Activity Relationship