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

• Published in: Bioorganic & medicinal chemistry letters 2007-09, Vol.17 (18), p.5041-5048
• Main Authors: Qiao, Jennifer X., Wang, Tammy C., Wang, Gren Z., Cheney, Daniel L., He, Kan, Rendina, Alan R., Xin, Baomin, Luettgen, Joseph M., Knabb, Robert M., Wexler, Ruth R., Lam, Patrick Y.S.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biological Availability; Blood. Blood coagulation. Reticuloendothelial system; Dogs; Enantiopure cyclicdiamine derivatives; Factor Xa Inhibitors; Half-Life; Human liver microsomal stability; Humans; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; SAR; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacokinetics; Serine Proteinase Inhibitors - pharmacology; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.07.020

We previously reported a series of enantiopure cis-(1 R,2 S)-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. (3 R,4 S)-Pyrrolidinyldiamide 31 was the best overall compound with a human FXa K i of 0.50 nM, a PT EC 2x of 2.1 μM in human plasma, a bioavailability of 25%, and a t 1/2 of 2.7 h in dogs. Further biochemical characterization of compound 31 is also presented. We previously reported a series of enantiopure cis-(1 R,2 S)-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. (3 R,4 S)-Pyrrolidinyldiamide 31 was the best overall compound with human FXa K i of 0.50 nM, PT EC 2x of 2.1 μM in human plasma, bioavailability of 25% and t 1/2of 2.7 h in dogs. Further biochemical characterization of compound 31 is also presented.