Discovery of (R)-6-Cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a Pote

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• 作者：Hui Li* ; John Tatlock ; Angelica Linton ; Javier Gonzalez ; Tanya Jewell ; Leena Patel ; Sarah Ludlum ; Matthew Drowns ; Sadayappan V. Rahavendran ; Heather Skor ; Robert Hunter ; Stephanie T. Shi ; Koleen J. He
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：March 12, 2009
• 年：2009
• 卷：52
• 期：5
• 页码：1255-1258
• 全文大小：149K
• 年卷期：v.52,no.5(March 12, 2009)
• ISSN：1520-4804

文摘

The HCV RNA-dependent RNA polymerase has emerged as one of the key targets for novel anti-HCV therapy development. Herein, we report the optimization of the dihydropyrone series inhibitors to improve compound aqueous solubility and reduce CYP2D6 inhibition, which led to the discovery of compound 24 (PF-00868554). Compound 24 is a potent and selective HCV polymerase inhibitor with a favorable pharmacokinetic profile and has recently entered a phase II clinical evaluation in patients with genotype 1 HCV.