title: Discovery and early development of TMC647055, a non-nucleoside inhibitor of the hepatitis C virus NS5B polymerase.
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.
authors.affiliation: Janssen Infectious Diseases BVBA (formerly Tibotec BVBA), Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Cummings
authors.forename: Tse-I
authors.initials: TI
authors.lastname: Lin
authors.forename: Lili
authors.initials: L
authors.lastname: Hu
authors.forename: Abdellah
authors.initials: A
authors.lastname: Tahri
authors.forename: David
authors.initials: D
authors.lastname: McGowan
authors.forename: Katie
authors.initials: K
authors.lastname: Amssoms
authors.forename: Stefaan
authors.initials: S
authors.lastname: Last
authors.forename: Benoit
authors.initials: B
authors.lastname: Devogelaere
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Rouan
authors.forename: Leen
authors.initials: L
authors.lastname: Vijgen
authors.forename: Jan Martin
authors.initials: JM
authors.lastname: Berke
authors.forename: Pascale
authors.initials: P
authors.lastname: Dehertogh
authors.forename: Els
authors.initials: E
authors.lastname: Fransen
authors.forename: Erna
authors.initials: E
authors.lastname: Cleiren
authors.forename: Liesbet
authors.initials: L
authors.lastname: van der Helm
authors.forename: Gregory
authors.initials: G
authors.lastname: Fanning
authors.forename: Origène
authors.initials: O
authors.lastname: Nyanguile
authors.forename: Kenny
authors.initials: K
authors.lastname: Simmen
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Remoortere
authors.forename: Pierre
authors.initials: P
authors.lastname: Raboisson
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vendeville
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C575713:27-cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-11,17-dimethyl-10,10-dioxide-2,19-methano-3,7:4,1-dimetheno-1H,11H-14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9H,15H)-dione; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase