title: 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.
abstract: 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.
authors.affiliation: Discovery Chemistry Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA. Donald.Pinto@bms.com
authors.forename: Donald J P
authors.initials: DJ
authors.lastname: Pinto
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Orwat
authors.forename: Mimi L
authors.initials: ML
authors.lastname: Quan
authors.forename: Qi
authors.initials: Q
authors.lastname: Han
authors.forename: Robert A
authors.initials: RA
authors.lastname: Galemmo
authors.forename: Eugene
authors.initials: E
authors.lastname: Amparo
authors.forename: Brian
authors.initials: B
authors.lastname: Wells
authors.forename: Christopher
authors.initials: C
authors.lastname: Ellis
authors.forename: Ming Y
authors.initials: MY
authors.lastname: He
authors.forename: Richard S
authors.initials: RS
authors.lastname: Alexander
authors.forename: Karen A
authors.initials: KA
authors.lastname: Rossi
authors.forename: Angela
authors.initials: A
authors.lastname: Smallwood
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.forename: Robert M
authors.initials: RM
authors.lastname: Knabb
authors.forename: Lawrence
authors.initials: L
authors.lastname: Mersinger
authors.forename: Charles
authors.initials: C
authors.lastname: Kettner
authors.forename: Steven
authors.initials: S
authors.lastname: Bai
authors.forename: Kan
authors.initials: K
authors.lastname: He
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.forename: Patrick Y S
authors.initials: PY
authors.lastname: Lam
mesh_terms: 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*
chemical_list: 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