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  • Title: Structure-activity relationship and pharmacokinetic profile of 5-ketopyrazole factor Xa inhibitors.
    Author: Varnes JG, Wacker DA, Pinto DJ, Orwat MJ, Theroff JP, Wells B, Galemo RA, Luettgen JM, Knabb RM, Bai S, He K, Lam PY, Wexler RR.
    Journal: Bioorg Med Chem Lett; 2008 Jan 15; 18(2):749-54. PubMed ID: 18054227.
    Abstract:
    Efforts to further optimize the clinical candidate razaxaban have led to a new series of pyrazole-based factor Xa (fXa) inhibitors. Designed to prevent the potential formation of primary aniline metabolites in vivo, the nitrogen of the carboxamido linker between the pyrazole and proximal phenyl moiety of the razaxaban scaffold was replaced with a methylene group. The resulting ketones demonstrated excellent potency and selectivity for fXa but initially had poor oral bioavailability. Optimization by conversion from a P1 aminobenzisoxazole to a P1 p-methoxyphenyl residue, replacing the 3-trifluoromethylpyrazole with a 3-amidopyrazole, and employing a pyridone P4 group provided a fXa inhibitor with a potency and pharmacokinetic profile equivalent to that of razaxaban and improved selectivity over thrombin.
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