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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Qiao JX, Wang TC, Wang GZ, Cheney DL, He K, Rendina AR, Xin B, Luettgen JM, Knabb RM, Wexler RR, Lam PY

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

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

PubMed ID

17643988 [ View in PubMed

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Abstract

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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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
5-CHLORO-N-((1R,2S)-2-(4-(2-OXOPYRIDIN-1(2H)-YL)BENZAMIDO) CYCLOPENTYL)THIOPHENE-2-CARBOXAMIDE	Coagulation factor X	Ki (nM)	0.43	N/A	N/A	Details