Andrew Pudzianowski - 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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      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. Journal of   Medicinal Chemistry 2008 51 (23)   7541-7551

      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 (IC50 = 2.4 nM, EC2xPT =   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.

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