Design, Structure−Activity Relationships, X-ray Crystal Structure, and Energetic Contributions of a Critical P1 Pharmacophore: 3-Chloroindole-7-yl-Based Factor Xa Inhibitors

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• 作者：Yan Shi ; Doree Sitkoff ; Jing Zhang ; Herbert E. Klei ; Kevin Kish ; Eddie C.-K. Liu ; Karen S. Hartl ; Steve M. Seiler ; Ming Chang ; Christine Huang ; Sonia Youssef ; Thomas E. Steinbacher ; William A. Schumac
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：December 11, 2008
• 年：2008
• 卷：51
• 期：23
• 页码：7541-7551
• 全文大小：370K
• 年卷期：v.51,no.23(December 11, 2008)
• ISSN：1520-4804

文摘

An indole-based P1 moiety was incorporated into a previously established factor Xa inhibitor series. The indole group was designed to hydrogen-bond with the carbonyl of Gly218, while its 3-methyl or 3-chloro substituent was intended to interact with Tyr228. These interactions were subsequently observed in the X-ray crystal structure of compound 18. SAR studies led to the identification of compound 20 as the most potent FXa inhibitor in this series (IC₅₀ = 2.4 nM, EC_2xPT = 1.2 μM). An in-depth energetic analysis suggests that the increased binding energy of 3-chloroindole-versus 3-methylindole-containing compounds in this series is due primarily to (a) the more hydrophobic nature of chloro- versus methyl-containing compounds and (b) an increased interaction of 3-chloroindole versus 3-methylindole with Gly218 backbone. The stronger hydrophobicity of chloro- versus methyl-substituted aromatics may partly explain the general preference for chloro- versus methyl-substituted P1 groups in FXa, which extends beyond the current series.