Optimization of the beta-aminoester class of factor Xa inhibitors. Part 1: P(4) and side-chain modifications for improved in vitro potency.
A systematic modification of the C(3) side-chain of the beta-aminoester class of factor Xa inhibitors and a survey of P(4) variations is described. These changes have resulted in the identification of sub-nanomolar inhibitors with improved selectivity versus related proteases. Coagulation parameters (i.e., APTT doubling concentrations) are also improved.
Czekaj
Mark
M
Drug Innovation and Approval, Aventis Pharmaceuticals, Route 202-206, Bridgewater, NJ 08807, USA. mark.czekaj@aventis.com
Klein
Scott I
SI
Guertin
Kevin R
KR
Gardner
Charles J
CJ
Zulli
Allison L
AL
Pauls
Henry W
HW
Spada
Alfred P
AP
Cheney
Daniel L
DL
Brown
Karen D
KD
Colussi
Dennis J
DJ
Chu
Valeria
V
Leadley
Robert J
RJ
Dunwiddie
Christopher T
CT
D004952:Esters; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
D004952:Esters; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors