کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1377516 | 981981 | 2007 | 8 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Enantiopure five-membered cyclicdiamine derivatives as potent and selective inhibitors of factor Xa. Improving in vitro metabolic stability via core modifications Enantiopure five-membered cyclicdiamine derivatives as potent and selective inhibitors of factor Xa. Improving in vitro metabolic stability via core modifications](/preview/png/1377516.png)
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 Ki of 0.50 nM, PT EC2x of 2.1 μM in human plasma, bioavailability of 25% and t1/2of 2.7 h in dogs. Further biochemical characterization of compound 31 is also presented.
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 a human FXa Ki of 0.50 nM, a PT EC2x of 2.1 μM in human plasma, a bioavailability of 25%, and a t1/2 of 2.7 h in dogs. Further biochemical characterization of compound 31 is also presented.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 17, Issue 18, 15 September 2007, Pages 5041–5048