Optimization of the beta-aminoester class of factor Xa inhibitors. Part 2: Identification of FXV673 as a potent and selective inhibitor with excellent In vivo anticoagulant activity.
Further optimization of the beta-aminoester class of factor Xa (fXa) inhibitors is described culminating in the identification of 9c (FXV673), a potent and selective factor Xa inhibitor with excellent in vivo anticoagulant activity. An X-ray structure of FXV673 bound to human fXa is also presented. Based on its selectivity, potent in vivo activity and favorable pre-clinical safety profile, FXV673 was selected for further development and is currently undergoing clinical trials.
Guertin
Kevin R
KR
Drug Innovation and Approval, Aventis Pharmaceuticals, Route 202-206, Bridgewater, NJ 08807, USA. kevin.guertin@roche.com
Gardner
Charles J
CJ
Klein
Scott I
SI
Zulli
Allison L
AL
Czekaj
Mark
M
Gong
Yong
Y
Spada
Alfred P
AP
Cheney
Daniel L
DL
Maignan
Sebastian
S
Guilloteau
Jean-Pierre
JP
Brown
Karen D
KD
Colussi
Dennis J
DJ
Chu
Valeria
V
Heran
Christopher L
CL
Morgan
Suzanne R
SR
Bentley
Ross G
RG
Dunwiddie
Christopher T
CT
Leadley
Robert J
RJ
Pauls
Henry W
HW
D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D003497:Cyclic N-Oxides / Q000737:chemistry* / Q000494:pharmacology*; D004952:Esters; D065427:Factor Xa Inhibitors; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
D000925:Anticoagulants; D003497:Cyclic N-Oxides; D004952:Esters; D065427:Factor Xa Inhibitors; D011725:Pyridines; D015842:Serine Proteinase Inhibitors; C435830:otamixaban