Discovery of ABT-267, a Pan-Genotypic Inhibitor of HCV NS5A

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• 作者：David A. DeGoey ; John T. Randolph ; Dachun Liu ; John Pratt ; Charles Hutchins ; Pamela Donner ; A. Chris Krueger ; Mark Matulenko ; Sachin Patel ; Christopher E. Motter ; Lissa Nelson ; Ryan Keddy ; Michael Tufano ; Daniel D. Caspi ; Preethi Krishnan ; Neeta Mistry ; Gennadiy Koev ; Thomas J. Reisch ; Rubina Mondal ; Tami Pilot-Matias ; Yi Gao ; David W. A. Beno ; Clarence J. Maring ; Akhter Molla ; Emily Dumas ; Andrew Campbell ; Laura Williams ; Christine Collins ; Rolf Wagner ; Warren M. Kati
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 13, 2014
• 年：2014
• 卷：57
• 期：5
• 页码：2047-2057
• 全文大小：461K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

We describe here N-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds with 2S,5S stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to the 2R,5R analogues. Furthermore, the attachment of substituents at the 4-position of the central N-phenyl group resulted in compounds with improved potency. Substitution with tert-butyl, as in compound 38 (ABT-267), provided compounds with low-picomolar EC₅₀ values and superior pharmacokinetics. It was discovered that compound 38 was a pan-genotypic HCV inhibitor, with an EC₅₀ range of 1.7鈥?9.3 pM against GT1a, -1b, -2a, -2b, -3a, -4a, and -5a and 366 pM against GT6a. Compound 38 decreased HCV RNA up to 3.10 log₁₀ IU/mL during 3-day monotherapy in treatment-naive HCV GT1-infected subjects and is currently in phase 3 clinical trials in combination with an NS3 protease inhibitor with ritonavir (r) (ABT-450/r) and an NS5B non-nucleoside polymerase inhibitor (ABT-333), with and without ribavirin.