【文章名】(1R,2R)-N-(1-Cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3 -b)indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): A Potent and Highly Selective Cathepsin K Inhibitor for the Treatment of Osteoarthritis
(1R,2R)-N-(1-Cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3 -b)indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): A Potent and Highly Selective Cathepsin K Inhibitor for the Treatment of Osteoarthritis
作者
DOSSETTER ALEXANDER G; BEELEY HOWARD; BOWYER JONATHAN; COOK CALUM R; CRAWFORD JAMES J; FINLAYSON JONATHAN E; HERON NICOLA M; HEYES CHRISTINE; HIGHTON ADRIAN J; HUDSON JULIAN A; JESTEL ANJA; KENNY PETER W; KRAPP STEPHAN; MARTIN SCOTT; MACFAUL PHILIP A; MCGUIRE THOMAS M; GUTIERREZ PABLO MORENTIN; MORLEY ANDREW D; MORRIS JEFFREY J; PAGE KEN M; RIBEIRO LYN ROSENBRIER; SAWNEY HELEN; STEINBACHER STEFAN; SMITH CAROLINE; VICKERS MADELEINE
[摘要]：Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.
