Discovery and early development of TMC647055, a non-nucleoside inhibitor of the hepatitis C virus NS5B polymerase

  • J Med Chem. 2014 Mar 13;57(5):1880-92. doi: 10.1021/jm401396p.
Maxwell D Cummings  1 ,  Tse-I Lin ,  Lili Hu ,  Abdellah Tahri ,  David McGowan ,  Katie Amssoms ,  Stefaan Last ,  Benoit Devogelaere ,  Marie-Claude Rouan ,  Leen Vijgen ,  Jan Martin Berke ,  Pascale Dehertogh ,  Els Fransen ,  Erna Cleiren ,  Liesbet van der Helm ,  Gregory Fanning ,  Origène Nyanguile ,  Kenny Simmen ,  Pieter Van Remoortere ,  Pierre Raboisson ,  Sandrine Vendeville
Affiliations
  • 1. Janssen Infectious Diseases BVBA (formerly Tibotec BVBA), Turnhoutseweg 30, 2340 Beerse, Belgium.
PMID: 24144360 DOI: 10.1021/jm401396p
Abstract

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 (i) 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.