1-[3-Aminobenzisoxazol-5'-yl]-3-trifluoromethyl-6-[2'-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1']-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one (BMS-740808) a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa.
Attempts to further optimize the pyrazole factor Xa inhibitors centered on masking the aryl aniline P4 moiety. Scaffold optimization resulted in the identification of a novel bicyclic pyrazolo-pyridinone scaffold which retained fXa potency. The novel bicyclic scaffold preserved all binding interactions observed with the monocyclic counterpart and importantly the carboxamido moiety was integrated within the scaffold making it less susceptible to hydrolysis. These efforts led to the identification of 1-[3-aminobenzisoxazol-5'-yl]-3-trifluoromethyl-6-[2'-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1']-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one 6f (BMS-740808), a highly potent (fXa Ki=30 pM) with a rapid onset of inhibition (2.7x10(7) M-1 s-1) in vitro, selective (>1000-fold over other proteases), efficacious in the AVShunt thrombosis model, and orally bioavailable inhibitor of blood coagulation factor Xa.
Pinto
Donald J P
DJ
Discovery Chemistry Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA. Donald.Pinto@bms.com
Orwat
Michael J
MJ
Quan
Mimi L
ML
Han
Qi
Q
Galemmo
Robert A
RA
Amparo
Eugene
E
Wells
Brian
B
Ellis
Christopher
C
He
Ming Y
MY
Alexander
Richard S
RS
Rossi
Karen A
KA
Smallwood
Angela
A
Wong
Pancras C
PC
Luettgen
Joseph M
JM
Rendina
Alan R
AR
Knabb
Robert M
RM
Mersinger
Lawrence
L
Kettner
Charles
C
Bai
Steven
S
He
Kan
K
Wexler
Ruth R
RR
Lam
Patrick Y S
PY
D065427:Factor Xa Inhibitors; D008958:Models, Molecular; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011728:Pyridones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
C513210:1-(3-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-6-(2'-(3-hydroxy-N-pyrrolidinyl)methyl-(1,1')-biphen-4-yl)-1,4,5,6-tetrahydropyrazolo-(3,4-c)-pyridin-7-one; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; D015842:Serine Proteinase Inhibitors