Highly efficacious factor Xa inhibitors containing alpha-substituted phenylcycloalkyl P4 moieties.
We previously disclosed a series of highly potent FXa inhibitors bearing alpha-substituted (CH(2)NR(1)R(2)) phenylcyclopropyl P4 moieties in the pyrazolodihydropyridone core system. Herein, we describe our continuous SAR efforts in this series. Effects of the C-3 substitution of the pyrazolodihydropyridone core and the alpha-substitution (R group) of the cyclopropyl ring on FXa binding affinity (FXa K(i)), human plasma anticoagulant activity (PT EC(2x)) and permeability are discussed. A set of compounds obtained from optimization of the R group and the C-3 substituent were orally bioavailable in dogs. Furthermore, representative compounds were highly efficacious in the rabbit arterio-venous shunt thrombosis model (EC(50)s=29-81nM).
Qiao
Jennifer X
JX
Research and Discovery, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543-5400, USA. jennifer.qiao@bms.com
King
Sarah R
SR
He
Kan
K
Wong
Pancras C
PC
Rendina
Alan R
AR
Luettgen
Joseph M
JM
Xin
Baomin
B
Knabb
Robert M
RM
Wexler
Ruth R
RR
Lam
Patrick Y S
PY
D000818:Animals; D018938:Caco-2 Cells; D065427:Factor Xa Inhibitors; D006801:Humans; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D065427:Factor Xa Inhibitors; D011728:Pyridones; D015842:Serine Proteinase Inhibitors