Inhibitors of the Hepatitis C Virus NS3 Protease with Basic Amine Functionality at the P3-Amino Acid N-Terminus: Discovery and Optimization of a New Series of P2−P4 Macrocycles

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• 作者：Steven Harper ; Marco Ferrara ; Benedetta Crescenzi ; Marco Pompei ; Maria Cecilia Palumbi ; Jillian M. DiMuzio ; Monica Donghi ; Fabrizio Fiore ; Uwe Koch ; Nigel J. Liverton ; Silvia Pesci ; Alessia Petrocchi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：August 13, 2009
• 年：2009
• 卷：52
• 期：15
• 页码：4820-4837
• 全文大小：1325K
• 年卷期：v.52,no.15(August 13, 2009)
• ISSN：1520-4804

文摘

In a follow-up to our recent disclosure of P2−P4 macrocyclic inhibitors of the hepatitis C virus (HCV) NS3 protease (e.g., 1, Chart 1), we report a new but related compound series featuring a basic amine at the N-terminus of the P3-amino acid residue. Replacement of the electroneutral P3-amino acid capping group (which is a feature of almost all tripeptide-like inhibitors of NS3 reported to date) with a basic group is not only tolerated but can result in advantageous cell based potency. Optimization of this new class of P3-amine based inhibitors gave compounds such as 25 and 26 that combine excellent cell based activity with pharmacokinetic properties that are attractive for an antiviral targeting HCV.