Synthesis and Biological Characterization of Aryl Uracil Inhibitors of Hepatitis C Virus NS5B Polymerase: Discovery of ABT-072, a trans-Stilbene Analog with Good Oral Bioavailability

  • J Med Chem. 2018 Feb 8;61(3):1153-1163. doi: 10.1021/acs.jmedchem.7b01630.
John T Randolph  1 ,  A Chris Krueger  1 ,  Pamela L Donner  1 ,  John K Pratt  1 ,  Dachun Liu  1 ,  Christopher E Motter  1 ,  Todd W Rockway  1 ,  Michael D Tufano  1 ,  Rolf Wagner  1 ,  Hock B Lim  1 ,  Jill M Beyer  1 ,  Rubina Mondal  1 ,  Neeta S Panchal  1 ,  Lynn Colletti  1 ,  Yaya Liu  1 ,  Gennadiy Koev  1 ,  Warren M Kati  1 ,  Lisa E Hernandez  1 ,  David W A Beno  1 ,  Kenton L Longenecker  1 ,  Kent D Stewart  1 ,  Emily O Dumas  1 ,  Akhteruzzaman Molla  1 ,  Clarence J Maring  1
Affiliations
  • 1. Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States.
PMID: 29342358 DOI: 10.1021/acs.jmedchem.7b01630
Abstract

ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV Infection. This compound was identified during a medicinal chemistry effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compound permeability and solubility and provided much better pharmacokinetic properties in preclinical species. Replacement of the dihydrouracil in 1 with an N-linked uracil provided better potency in the genotype 1 replicon assay. Results from phase 1 clinical studies supported once-daily oral dosing with ABT-072 in HCV infected patients. A phase 2 clinical study that combined ABT-072 with the HCV Protease Inhibitor ABT-450 provided a sustained virologic response at 24 weeks after dosing (SVR24) in 10 of 11 patients who received treatment.

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