Discovery and Preclinical
Characterization of the
Cyclopropylindolobenzazepine BMS-791325, A Potent Allosteric Inhibitor
of the Hepatitis C Virus NS5B Polymerase
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Abstract
Described herein are structure–activity
relationship studies
that resulted in the optimization of the activity of members of a
class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors.
Subsequent iterations of analogue design and syntheses successfully
addressed off-target activities, most notably human pregnane X receptor
(hPXR) transactivation, and led to significant improvements in the
physicochemical properties of lead compounds. Those analogues exhibiting
improved solubility and membrane permeability were shown to have notably
enhanced pharmacokinetic profiles. Additionally, a series of alkyl
bridged piperazine carboxamides was identified as being of particular
interest, and from which the compound BMS-791325 (<b>2</b>)
was found to have distinguishing antiviral, safety, and pharmacokinetic
properties that resulted in its selection for clinical evaluation