High potency improvements to weak aryl uracil HCV polymerase inhibitor leads

详细信息    查看全文

• 作者：Pamela Donner ; John T. R ; olph ; Peggy Huang ; Rolf Wagner ; Clarence Maring ; Ben Hock Lim ; Lynn Colletti ; Yaya Liu ; Rubina Mondal ; Jill Beyer ; Gennadiy Koev ; Kennan Marsh ; David Beno ; Kenton Longenecker ; Tami Pilot-Matias ; Warren Kati ; Akhter Molla ; Dale Kempf
• 关键词：HCV ; NS5B polymerase ; Aryl-uracil
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：1 August, 2013
• 年：2013
• 卷：23
• 期：15
• 页码：4367-4369
• 全文大小：1080 K

文摘

Described herein is the development of a potent non-nucleoside, small molecule inhibitor of genotype 1 HCV NS5B Polymerase. A 23 ¦ÌM inhibitor that was active against HCV polymerase was further elaborated into a potent single-digit nanomolar inhibitor of HCV NS5B polymerase by additional manipulation of the R and R₁ substituents. Subsequent modifications to improve physical properties were made in an attempt to achieve an acceptable pharmacokinetic profile.