9-Hydroxyazafluorenes and their use in thrombin inhibitors

…, PG Nantermet, CL Newton, CF Homnick…

文献索引：Stauffer, Kenneth J.; Williams, Peter D.; Selnick, Harold G.; Nantermet, Philippe G.; Newton, Christina L.; Homnick, Carl F.; Zrada, Matthew M.; Lewis, S. Dale; Lucas, Bobby J.; Krueger, Julie A.; Pietrak, Beth L.; Lyle, Elizabeth A.; Singh, Rominder; Miller-Stein, Cynthia; White, Rebecca B.; Wong, Bradley; Wallace, Audrey A.; Sitko, Gary R.; Cook, Jacquelyn J.; Holahan, Marie A.; Stranieri-Michener, Maria; Leonard, Yvonne M.; Lynch Jr., Joseph J.; McMasters, Daniel R.; Yan, Youwei Journal of Medicinal Chemistry, 2005 , vol. 48, # 7 p. 2282 - 2293

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被引用次数: 23

摘要

Optimization of a previously reported thrombin inhibitor, 9-hydroxy-9-fluorenylcarbonyl-l- prolyl-trans-4-aminocyclohexylmethylamide (1), by replacing the aminocyclohexyl P1 group provided a new lead structure, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-2-aminomethyl-5- chlorobenzylamide (2), with improved potency (K i= 0.49 nM for human thrombin, 2× APTT= 0.37 μM in human plasma) and pharmacokinetic properties (F= 39%, iv T 1/2= 13 h in ...