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 |
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Authors: | Pinto Donald J P Orwat Michael J Quan Mimi L Han Qi Galemmo Robert A Amparo Eugene Wells Brian Ellis Christopher He Ming Y Alexander Richard S Rossi Karen A Smallwood Angela Wong Pancras C Luettgen Joseph M Rendina Alan R Knabb Robert M Mersinger Lawrence Kettner Charles Bai Steven He Kan Wexler Ruth R Lam Patrick Y S |
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Institution: | Discovery Chemistry Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA. Donald.Pinto@bms.com |
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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. |
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