Factor Xa Inhibitors: S1 Binding Interactions of a Series of N-{(3S)-1-[(1S)-1-Methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides
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- 作者：Chuen Chan ; Alan D. Borthwick ; David Brown ; Cynthia L. Burns-Kurtis ; Matthew Campbell ; Laiq Chaudry ; Chun-wa Chung ; Má ; ire A. Convery ; J. Nicole Hamblin ; Lisa Johnstone ; Henry A. Kelly ; Savvas K
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：April 5, 2007
- 年：2007
- 卷：50
- 期：7
- 页码：1546 - 1557
- 全文大小：454K
- 年卷期：v.50,no.7(April 5, 2007)
- ISSN：1520-4804
文摘
Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight intobinding interactions within the S1 primary specificity pocket; rationales are presented for the derived SARon the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecularmodeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and theextent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokineticprofiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as acandidate for further evaluation.