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,

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• 作者：Donald J. P. Pinto ; Michael J. Orwat ; Stephanie Koch ; Karen A. Rossi ; Richard S. Alexander ; Angela Smallwood ; Pancras C. Wong ; Alan R. Rendina ; Joseph M. Luettgen ; Robert M. Knabb ; Kan He ; Baomin Xin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 1, 2007
• 年：2007
• 卷：50
• 期：22
• 页码：5339 - 5356
• 全文大小：489K
• 年卷期：v.50,no.22(November 1, 2007)
• ISSN：1520-4804

文摘

Efforts to identify a suitable follow-on compound to razaxaban (compound 4) focused on modification ofthe carboxamido linker to eliminate potential in vivo hydrolysis to a primary aniline. Cyclization of thecarboxamido linker to the novel bicyclic tetrahydropyrazolopyridinone scaffold retained the potent fXa bindingactivity. Exceptional potency of the series prompted an investigation of the neutral P₁ moieties that resultedin the identification of the p-methoxyphenyl P₁, which retained factor Xa binding affinity and good oralbioavailability. Further optimization of the C-3 pyrazole position and replacement of the terminal P₄ ringwith a neutral heterocycle culminated in the 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, compound 40). Compound 40 exhibits a high degree of fXa potency, selectivity, and efficacy and has an improved pharmacokineticprofile relative to 4.