Discovery of BI 207524, an Indole Diamide NS5B Thumb Pocket 1 Inhibitor with Improved Potency for the Potential Treatment of Chronic Hepatitis C Virus Infection
详细信息 查看全文
- 作者：Pierre L. Beaulieu ; Paul C. Anderson ; Richard Bethell ; Michael B枚s ; Yves Bousquet ; Christian Brochu ; Michael G. Cordingley ; Gulrez Fazal ; Michel Garneau ; James R. Gillard ; Stephen Kawai ; Martin Marquis ; Ginette McKercher ; Marc-Andr茅 Poupart ; Timothy Stammers ; Bounkham Thavonekham ; Dominik Wernic ; Jianmin Duan ; George Kukolj
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：December 11, 2014
- 年：2014
- 卷：57
- 期：23
- 页码：10130-10143
- 全文大小：552K
- ISSN：1520-4804
文摘
The development of interferon-free regimens for the treatment of chronic HCV infection constitutes a preferred option that is expected in the future to provide patients with improved efficacy, better tolerability, and reduced risk for emergence of drug-resistant virus. We have pursued non-nucleoside NS5B polymerase allosteric inhibitors as combination partners with other direct acting antivirals (DAAs) having a complementary mechanism of action. Herein, we describe the discovery of a potent follow-up compound (BI 207524, 27) to the first thumb pocket 1 NS5B inhibitor to demonstrate antiviral activity in genotype 1 HCV infected patients, BILB 1941 (1). Cell-based replicon potency was significantly improved through electronic modulation of the pKa of the carboxylic acid function of the lead molecule. Subsequent ADME-PK optimization lead to 27, a predicted low clearance compound in man. The preclinical profile of inhibitor 27 is discussed, as well as the identification of a genotoxic metabolite that led to the discontinuation of the development of this compound.