Non-nucleoside Inhibitors of the Measles Virus RNA-Dependent RNA Polymerase: Synthesis, Structure鈥揂ctivity Relationships, and Pharmacokinetics

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• 作者：J. Maina Ndungu ; Stefanie A. Krumm ; Dan Yan ; Richard F. Arrendale ; G. Prabhakar Reddy ; Taylor Evers ; Randy Howard ; Michael G. Natchus ; Manohar T. Saindane ; Dennis C. Liotta ; Richard K. Plemper ; James P. Snyder ; Aiming Sun
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 10, 2012
• 年：2012
• 卷：55
• 期：9
• 页码：4220-4230
• 全文大小：537K
• 年卷期：v.55,no.9(May 10, 2012)
• ISSN：1520-4804

文摘

The measles virus (MeV), a member of the paramyxovirus family, is an important cause of pediatric morbidity and mortality worldwide. In an effort to provide therapeutic treatments for improved measles management, we previously identified a small, non-nucleoside organic inhibitor of the viral RNA-dependent RNA polymerase by means of high-throughput screening. Subsequent structure鈥揳ctivity relationship (SAR) studies around the corresponding pyrazole carboxamide scaffold led to the discovery of 2 (AS-136a), a first generation lead with low nanomolar potency against life MeV and attractive physical properties suitable for development. However, its poor water solubility and low oral bioavailability (F) in rat suggested that the lead could benefit from further SAR studies to improve the biophysical characteristics of the compound. Optimization of in vitro potency and aqueous solubility led to the discovery of 2o (ERDRP-00519), a potent inhibitor of MeV (EC₅₀ = 60 nM) with an aqueous solubility of approximately 60 渭g/mL. The agent shows a 10-fold exposure (AUC/C_max) increase in the rat model relative to 2, displays near dose proportionality in the range of 10鈥?0 mg/kg, and exhibits good oral bioavailability (F = 39%). The significant solubility increase appears linked to the improved oral bioavailability.