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
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OverviewOverview
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-pyr, rolidinyl)methyl-[1,1']-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-py, ridin-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.
DiseaseDisease
Known disease associated with this structure: Factor X deficiency OMIM:[227600]
About this StructureAbout this Structure
2FZZ is a Protein complex structure of sequences from Homo sapiens with 5QC as ligand. Active as Coagulation factor Xa, with EC number 3.4.21.6 Full crystallographic information is available from OCA.
ReferenceReference
1-[3-Aminobenzisoxazol-5'-yl]-3-trifluoromethyl-6-[2'-(3-(R)-hydroxy-N-pyr rolidinyl)methyl-[1,1']-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-py ridin-7-one (BMS-740808) a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa., Pinto DJ, Orwat MJ, Quan ML, Han Q, Galemmo RA Jr, Amparo E, Wells B, Ellis C, He MY, Alexander RS, Rossi KA, Smallwood A, Wong PC, Luettgen JM, Rendina AR, Knabb RM, Mersinger L, Kettner C, Bai S, He K, Wexler RR, Lam PY, Bioorg Med Chem Lett. 2006 Aug 1;16(15):4141-7. Epub 2006 May 30. PMID:16730984
Page seeded by OCA on Mon Nov 12 22:12:32 2007