Discovery of Ledipasvir (GS-5885): A Potent, Once-Daily Oral NS5A Inhibitor for the Treatment of Hepatitis C Virus Infection

作者：Link John O^*; Taylor James G; Xu Lianhong; Mitchell Michael; Guo Hongyan; Liu Hongtao; Kato Darryl; Kirschberg Thorsten; Sun Jianyu; Squires Neil; Parrish Jay; Keller Terry; Yang Zheng Yu; Yang Chris; Matles Mike; Wang Yujin; Wang Kelly; Cheng Guofeng; Tian Yang; Mogalian Erik; Mondou Elsa; Cornpropst Melanie; Perry Jason; Desai Manoj C

来源：Journal of Medicinal Chemistry, 2014, 57(5): 2033-2046.

DOI：10.1021/jm401499g

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 37-45 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 la 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.

• 出版日期2014-3-13