Design, Synthesis and Discovery of 1-(2-(6-Chloro-3-methylsulfonyl)-naphthyl)-1H-pyrazole-5-carboxylamides as Highly Potent Factor Xa Inhibitors

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概要

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• Based upon the biphenyl 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides reported in our previous communications, we designed and discovered 2-(6-chloro-3-methylsulfonyl)-naphthyl as an optimal factor Xa S1 binding element. Employing a key Diels–Alder reaction of 1,4-dihydro-2,3-benzoxathiin-3-oxide with maleic anhydride and a key Cu(I)-mediated methylsulfonylation, we prepared two biphenyl 1-(2-(6-chloro-3-methylsulfonyl)-naphthyl)-1H-pyrazole-5-carboxylamides as highly potent factor Xa inhibitors with Ki values of 0.065 nM and 0.045 nM respectively, and demonstrated the synergistically enhanced binding interaction in the factor Xa S1 site.

• 公益社団法人　日本薬学会の論文

著者

• Jia Zhaozhong

  Portola Pharmaceuticals, Inc.

• Scarborough Robert

  Portola Pharmaceuticals, Inc.

• Zhang Penglie

  ChemoCentryx, Inc.

• Halfon Sherin

  Relypsa, Inc.

• Arfsten Ann

  Genelabs Technologies, Inc.

• Sinha Uma

  Portola Pharmaceuticals, Inc.

• Zhu Bing-Yan

  Genentech, Inc.

関連論文

• Design, Synthesis and Discovery of 1-(2-(6-Chloro-3-methylsulfonyl)-naphthyl)-1H-pyrazole-5-carboxylamides as Highly Potent Factor Xa Inhibitors

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