title: Enantiopure five-membered cyclicdiamine derivatives as potent and selective inhibitors of factor Xa. Improving in vitro metabolic stability via core modifications.
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.
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, PO Box 5400, Princeton, NJ 08643-5400, USA. jennifer.qiao@bms.com
authors.forename: Jennifer X
authors.initials: JX
authors.lastname: Qiao
authors.forename: Tammy C
authors.initials: TC
authors.lastname: Wang
authors.forename: Gren Z
authors.initials: GZ
authors.lastname: Wang
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Cheney
authors.forename: Kan
authors.initials: K
authors.lastname: He
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.forename: Baomin
authors.initials: B
authors.lastname: Xin
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Robert M
authors.initials: RM
authors.lastname: Knabb
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.forename: Patrick Y S
authors.initials: PY
authors.lastname: Lam
mesh_terms: D000818:Animals; D001682:Biological Availability; D004285:Dogs; D065427:Factor Xa Inhibitors; D006207:Half-Life; D006801:Humans; D008958:Models, Molecular; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors