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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Authors: | Shi Yan Sitkoff Doree Zhang Jing Klei Herbert E Kish Kevin Liu Eddie C-K Hartl Karen S Seiler Steve M Chang Ming Huang Christine Youssef Sonia Steinbacher Thomas E Schumacher William A Grazier Nyeemah Pudzianowski Andrew Apedo Atsu Discenza Lorell Yanchunas Joseph Stein Philip D Atwal Karnail S |
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Affiliation: | Bristol-Myers Squibb Research & Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. yan.shi@bms.com |
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Abstract: | 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 (IC(50) = 2.4 nM, EC(2xPT) = 1.2 microM). 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. |
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