Medicinal Chemistry, ‡Drug Metabolism, §Biology, ±Formulation and Process Development, ∥Clinical Research, and ⊥Structural Chemistry, Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
J Med Chem. 2014 Mar 13;57(5):2033-46. doi: 10.1021/jm401499g. Epub 2014 Jan 10.
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.
一种新型的高活性 NS5A 抑制剂，具有非对称苯并咪唑-二氟二苯并呋喃-咪唑核心和远端[2.2.1]氮杂双环系统被发现。通过对抗病毒活性和药代动力学的优化，确定了 39（ledipasvir，GS-5885）。化合物 39（GT1a 复制子 EC50 = 31 pM）在健康志愿者中的血浆半衰期延长至 37-45 小时，并且在每日一次口服剂量为 3 毫克或更大剂量的单药治疗中，可迅速使病毒载量降低>3 对数，在基因型 1a HCV 感染患者中。在与具有互补机制的直接作用抗病毒药物联合使用时，39 已被证明是安全有效的，SVR12 率高达 100%。
