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Bioorg Med Chem Lett. 2007 Sep 15;17(18):5041-8. Epub 2007 Jul 13.

Enantiopure five-membered cyclicdiamine derivatives as potent and selective inhibitors of factor Xa. Improving in vitro metabolic stability via core modifications.

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Bristol-Myers Squibb Company, Research and Development, PO Box 5400, Princeton, NJ 08643-5400, USA.


We previously reported a series of enantiopure cis-(1R,2S)-cyclopentyldiamine derivatives as potent and selective inhibitors of Factor Xa (FXa). Herein, we describe our approach to improve the metabolic stability of this series via core modifications. Multiple resulting series of compounds demonstrated similarly high FXa potency and improved metabolic stability in human liver microsomes compared with the cyclopentyldiamide 1. (3R,4S)-Pyrrolidinyldiamide 31 was the best overall compound with human FXa K(i) of 0.50 nM, PT EC(2x) of 2.1 microM in human plasma, bioavailability of 25% and t(1/2)of 2.7h in dogs. Further biochemical characterization of compound 31 is also presented.

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