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：344

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.

引用

页码：5339 / 5356

页数：18

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