Discovery and Early Development of TMC647055, a Non-Nucleoside Inhibitor of the Hepatitis C Virus NS5B Polymerase

作者：Cummings Maxwell D; Lin Tse I; Hu Lili; Tahri Abdellah; McGowan David; Amssoms Katie; Last Stefaan; Devogelaere Benoit; Rouan Marie Claude; Vijgen Leen; Berke Jan Martin; Dehertogh Pascale; Fransen Els; Cleiren Erna; van der Helm Lie**et; Fanning Gregory; Nyanguile Origene; Simmen Kenny; Van Remoortere Pieter; Raboisson Pierre; Vendeville Sandrine^*

来源：Journal of Medicinal Chemistry, 2014, 57(5): 1880-1892.

DOI：10.1021/jm401396p

Structure-based macrocyclization of a 6-carboxylic acid indole chemotype has yielded potent and selective finger-loop inhibitors of the hepatitis C virus (HCV) NS5B polymerase. Lead optimization in conjunction with in vivo evaluation in rats identified several compounds showing 0) nanomolar potency in HCV replicon cells, (ii) limited toxicity and off-target activities, and (iii) encouraging preclinical pharmacokinetic profiles characterized by high liver distribution. This effort culminated in the identification of TMC647055 (10a), a nonzwitterionic 17-membered-ring macrocycle characterized by high affinity, long polymerase residence time, and broad genotypic coverage. In vitro results of the combination of 10a with the HCV protease inhibitor TMC435 (simeprevir) supported an evaluation of this combination in patients with regard to virus suppression and resistance emergence. In a phase 1b trial with HCV genotype 1-infected patients, 10a was considered to be safe and well-tolerated and demonstrated potent antiviral activity, which was further enhanced in a combination study with TMC435.

• 出版日期2014-3-13