2FZZ

Factor Xa in complex with the inhibitor 1-(3-amino-1,2-benzisoxazol-5-yl)-6-(2'-(((3r)-3-hydroxy-1-pyrrolidinyl)methyl)-4-biphenylyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7h-pyrazolo[3,4-c]pyridin-7-one

Summary for 2FZZ

• Entry DOI: 10.2210/pdb2fzz/pdb
• Descriptor: Coagulation factor X, 1-(3-AMINO-1,2-BENZISOXAZOL-5-YL)-6-(2'-{[(3R)-3-HYDROXYPYRROLIDIN-1-YL]METHYL}BIPHENYL-4-YL)-3-(TRIFLUOROMETHYL)-1,4,5,6-TETRAHYDRO-7H-PYRAZOLO[3,4-C]PYRIDIN-7-ONE (3 entities in total)
• Functional Keywords: glycoprotein, hydrolase, serine protease, plasma, blood coagulation factor, protein inhibitor complex, calcium-binding
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P00742 P00742
• Total number of polymer chains: 2
• Total formula weight: 32624.92

Authors

Alexander, R.S. (deposition date: 2006-02-10, release date: 2006-06-27, Last modification date: 2024-10-30)

Primary citation

Pinto, D.J.,Orwat, M.J.,Quan, M.L.,Han, Q.,Galemmo, R.A.,Amparo, E.,Wells, B.,Ellis, C.,He, M.Y.,Alexander, R.S.,Rossi, K.A.,Smallwood, A.,Wong, P.C.,Luettgen, J.M.,Rendina, A.R.,Knabb, R.M.,Mersinger, L.,Kettner, C.,Bai, S.,He, K.,Wexler, R.R.,Lam, P.Y.
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.
Bioorg.Med.Chem.Lett., 16:4141-4147, 2006

PubMed 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.

PubMed: 16730984
DOI: 10.1016/j.bmcl.2006.02.069

Experimental method

X-RAY DIFFRACTION (2.2 Å)