Pyrazole-based factor Xa inhibitors containing N-arylpiperidinyl P4 residues.
The synthesis, SAR, pharmacokinetic profile, and modeling studies of both monocyclic and fused pyrazoles containing substituted N-arylpiperidinyl P4 moieties that are potent and selective factor Xa inhibitors will be discussed. Fused pyrazole analog 16a, with a 2'-methylsulfonylphenyl piperidine P4 group, was shown to be the best compound in this series (FXa Ki = 0.35 nM) based on potency, selectivity, and pharmacokinetic profile.
Qiao
Jennifer X
JX
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08543-5400, USA. jennifer.qiao@bms.com
Cheng
Xuhong
X
Smallheer
Joanne M
JM
Galemmo
Robert A
RA
Drummond
Spencer
S
Pinto
Donald J P
DJ
Cheney
Daniel L
DL
He
Kan
K
Wong
Pancras C
PC
Luettgen
Joseph M
JM
Knabb
Robert M
RM
Wexler
Ruth R
RR
Lam
Patrick Y S
PY
D000818:Animals; D004285:Dogs; D065427:Factor Xa Inhibitors; D008958:Models, Molecular; D010880:Piperidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011485:Protein Binding; D011720:Pyrazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship
D065427:Factor Xa Inhibitors; D010880:Piperidines; D011720:Pyrazoles