Enantiopure five-membered cyclicdiamine derivatives as potent and selective inhibitors of factor Xa. Improving in vitro metabolic stability via core modifications.
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.
Qiao
Jennifer X
JX
Bristol-Myers Squibb Company, Research and Development, PO Box 5400, Princeton, NJ 08643-5400, USA. jennifer.qiao@bms.com
Wang
Tammy C
TC
Wang
Gren Z
GZ
Cheney
Daniel L
DL
He
Kan
K
Rendina
Alan R
AR
Xin
Baomin
B
Luettgen
Joseph M
JM
Knabb
Robert M
RM
Wexler
Ruth R
RR
Lam
Patrick Y S
PY
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
D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors