Discovery of potent, efficacious, and orally bioavailable inhibitors of blood coagulation factor Xa with neutral P1 moieties.
The bicyclic dihydropyrazolopyridinone scaffold allowed for incorporation of multiple P1 moieties with subnanomolar binding affinities for blood coagulation factor Xa. The compound 3-[6-(2'-dimethylaminomethyl-biphenyl-4-yl)-7-oxo-3-trifluoro-methyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridine-l-yl]-benzamide 6d shows good fXa potency, selectivity, in vivo efficacy and oral bioavailability. Compound 6d was selected for further pre-clinical evaluations.
Pinto
Donald J P
DJ
Discovery Chemistry Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA. Donald.Pinto@bms.com
Galemmo
Robert A
RA
Quan
Mimi L
ML
Orwat
Michael J
MJ
Clark
Charles
C
Li
Renhua
R
Wells
Brian
B
Woerner
Francis
F
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
He
Kan
K
Wexler
Ruth R
RR
Lam
Patrick Y S
PY
D000284:Administration, Oral; D001549:Benzamides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D016896:Treatment Outcome
D001549:Benzamides; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents