The discovery of glycine and related amino acid-based factor Xa inhibitors
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- 作者：Jeffrey T. Kohrt ; Kevin J. Filipski ; Wayne L. Cody ; Christopher F. Bigge ; Frances La ; Kathleen Welch ; Tawny Dahring ; John W. Bryant ; Daniele Leonard ; Gary Bolton et al.
- 关键词：Factor Xa inhibitor ; Antithrombotics
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2006
- 出版时间：1 July 2006
- 年：2006
- 卷：14
- 期：13
- 页码：4379-4392
- 全文大小：550 K
文摘
Herein, we report on the identification of three potent glycine and related amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl pharmacophore. A X-ray crystal structure has shown that constrained glycine derivatives with optimized N-substitution can greatly increase hydrophobic interactions in the FXa active site. Also, the substitution of a pyridone ring for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with enhanced oral bioavailability.