Design, Synthesis, and Evaluation of Oxygen-Containing Macrocyclic Peptidomimetics as Inhibitors of HCV NS3 Protease

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• 作者：Francisco Velzquez ; Srikanth Venkatraman ; Melissa Blackman ; Patrick Pinto ; Stphane Bogen ; Mousumi Sannigrahi ; Kevin Chen ; John Pichardo ; Andrea Hart ; Xiao Tong ; Viyyoor Girijavallabhan ; F. George Njoro
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：February 12, 2009
• 年：2009
• 卷：52
• 期：3
• 页码：700-708
• 全文大小：200K
• 年卷期：v.52,no.3(February 12, 2009)
• ISSN：1520-4804

文摘

HCV infection is considered a silent epidemic because most people infected do not develop acute symptoms. Instead, the disease progresses to a chronic state leading to cirrhosis and hepatocarcinoma. Novel therapies are needed to combat this major health threat. The HCV NS3 serine protease has been the target of continuous investigation because of its pivotal role in viral replication. Herein, we present the P1−P3 macrocyclization approach followed for identification of HCV NS3 inhibitors as potential backup candidates to our first generation drug candidate, Sch 503034 (1). Different P1−P3 linkers were investigated to identify novel macrocyclic scaffolds. SAR exploration of P3-caps in the macrocyclic cores allowed the identification of l-serine derived macrocycle 32 (K_i* = 3 nM, EC₉₀ = 30 nM) and allo-threonine derived macrocycle 36 (K_i* = 3 nM, EC₉₀ = 30 nM) as potent HCV NS3 protease inhibitors.