| Literature DB >> 24320933 |
John O Link1, James G Taylor, Lianhong Xu, Michael Mitchell, Hongyan Guo, Hongtao Liu, Darryl Kato, Thorsten Kirschberg, Jianyu Sun, Neil Squires, Jay Parrish, Terry Kellar, 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.
Abstract
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 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.Entities:
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Year: 2014 PMID： 24320933 DOI： 10.1021/jm401499g
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446