Publication Details (including relevant citation information):
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.
Address (URL): http://dx.doi.org/10.1021/jm800855x