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

• Published in: Journal of medicinal chemistry Vol. 57; no. 5; pp. 2033 - 2046
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.03.2014; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Antiviral Agents - administration & dosage; Antiviral Agents - pharmacokinetics; Antiviral Agents - therapeutic use; Base Sequence; Benzimidazoles - pharmacokinetics; Benzimidazoles - pharmacology; Benzimidazoles - therapeutic use; Chemistry, Medicinal; DNA Primers; Double-Blind Method; Fluorenes - pharmacokinetics; Fluorenes - pharmacology; Fluorenes - therapeutic use; Half-Life; Hepatitis C - drug therapy; Humans; Life Sciences & Biomedicine; Macaca fascicularis; Male; Pharmacology & Pharmacy; Placebos; Rats; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; Viral Nonstructural Proteins - antagonists & inhibitors; RESISTANCE; HCV; PROTEIN; PREDICTION
• ISSN: 0022-2623; 1520-4804
• 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 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.