Discovery of Ledipasvir (GS-5885): A Potent, Once-Daily Oral NS5A Inhibitor for the Treatment of Hepatitis C Virus Infection
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- 作者：John O. Link ; James G. Taylor ; Lianhong Xu ; Michael Mitchell ; Hongyan Guo ; Hongtao Liu ; Darryl Kato ; Thorsten Kirschberg ; Jianyu Sun ; Neil Squires ; Jay Parrish ; Terry Keller ; Zheng-Yu Yang ; Chris Yang ; Mike Matles ; Yujin Wang ; Kelly Wang ; Guofeng Cheng ; Yang Tian ; Erik Mogalian ; Elsa Mondou ; Melanie Cornpropst ; Jason Perry ; Manoj C. Desai
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：March 13, 2014
- 年：2014
- 卷：57
- 期：5
- 页码：2033-2046
- 全文大小：755K
- 年卷期：v.57,no.5(March 13, 2014)
- ISSN：1520-4804
文摘
A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered. Optimization of antiviral potency and pharmacokinetics led to the identification of 39 (ledipasvir, GS-5885). Compound 39 (GT1a replicon EC50 = 31 pM) has an extended plasma half-life of 37鈥?5 h in healthy volunteers and produces a rapid >3 log viral load reduction in monotherapy at oral doses of 3 mg or greater with once-daily dosing in genotype 1a HCV-infected patients. 39 has been shown to be safe and efficacious, with SVR12 rates up to 100% when used in combination with direct-acting antivirals having complementary mechanisms.