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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
Journal article   Peer reviewed

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

John T Randolph, A Chris Krueger, Pamela L Donner, John K Pratt, Dachun Liu, Christopher E Motter, Todd W Rockway, Michael D Tufano, Rolf Wagner, Hock B Lim, …
Journal of medicinal chemistry, Vol.61(3), pp.1153-1163
08/02/2018
DOI: https://doi.org/10.1021/acs.jmedchem.7b01630
PMID: 29342358

Abstract

Administration, Oral Biological Availability Chemistry Techniques, Synthetic Cytosine - analogs & derivatives Cytosine - chemical synthesis Cytosine - chemistry Cytosine - pharmacokinetics Cytosine - pharmacology Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Hepacivirus - enzymology Humans Permeability Stereoisomerism Stilbenes - chemistry Sulfonamides - chemical synthesis Sulfonamides - chemistry Sulfonamides - pharmacokinetics Sulfonamides - pharmacology Tissue Distribution Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - chemistry
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 (SVR ) in 10 of 11 patients who received treatment.

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