2. Academic Validation
  3. 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

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

Affiliation

  • 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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