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Cummings M.D.,Janssen Infectious Diseases BVBA Formerly Tibotec BVBA | Cummings M.D.,Janssen Research and Development | Lin T.-I.,Janssen Infectious Diseases BVBA Formerly Tibotec BVBA | Hu L.,Janssen Infectious Diseases BVBA Formerly Tibotec BVBA | And 20 more authors.
Angewandte Chemie - International Edition | Year: 2012

The concept of drug-likeness distills the physicochemical properties of small-molecule drugs to a set of rules. Macrocyclic drugs are known to break these rules. A structure-based macrocyclization strategy was applied to design new hepatitis C virus NS5B inhibitors with improved pharmacokinetic properties, exemplifying a rational strategy for overcoming the confines of standard "drug-like chemical space". Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Cummings M.D.,Janssen Infectious Diseases BVBA Formerly Tibotec BVBA | Cummings M.D.,Janssen Research and Development | Lin T.-I.,Janssen Infectious Diseases BVBA Formerly Tibotec BVBA | Lin T.-I.,Roche Holding AG | And 22 more authors.
Journal of Medicinal Chemistry | Year: 2014

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. © 2013 American Chemical Society. Source

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