Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa

被引：341
作者：
Pinto, Donald J. P. [1 ]
Orwat, Michael J. [1 ]
Koch, Stephanie [1 ]
Rossi, Karen A. [1 ]
Alexander, Richard S. [1 ]
Smallwood, Angela [1 ]
Wong, Pancras C. [1 ]
Rendina, Alan R. [1 ]
Luettgen, Joseph M. [1 ]
Knabb, Robert M. [1 ]
He, Kan [1 ]
Xin, Baomin [1 ]
Wexler, Ruth R. [1 ]
Lam, Patrick Y. S. [1 ]
机构：
[1] Bristol Myers Squibb Co, Pennsauken, NJ 08534 USA
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 22期
关键词：
D O I：
10.1021/jm070245n
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Efforts to identify a suitable follow-on compound to razaxaban (compound 4) focused on modification of the carboxamido linker to eliminate potential in vivo hydrolysis to a primary aniline. Cyclization of the carboxamido linker to the novel bicyclic tetrahydropyrazolopyridinone scaffold retained the potent fXa binding activity. Exceptional potency of the series prompted an investigation of the neutral P-1 moieties that resulted in the identification of the p-methoxyphenyl P-1, which retained factor Xa binding affinity and good oral bioavailability. Further optimization of the C-3 pyrazole position and replacement of the terminal P-4 ring with a neutral heterocycle culminated in the discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidinl-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, compound 40). Compound 40 exhibits a high degree of fXa potency, selectivity, and efficacy and has an improved pharmacokinetic profile relative to 4.
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收藏
页码：5339 / 5356
页数：18
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