Abstract
The discovery of beclabuvir occurred through an iterative series of structure-activity relationship studies directed at the optimization of a novel class of indolobenzazepines. Within this research, a strategic decision to abandon a highly potent but physiochemically problematic series in favor of one of lower molecular weight and potency was key in the realization of the program’s objectives. Subsequent cycles of analog design incorporating progressive conformational constraints successfully addressed off-target liabilities and identified compounds with improved physiochemical profiles. Ultimately, a class of alkyl-bridged piperazine carboxamides was found to be of particular interest, and from this series, beclabuvir was identified as having superior antiviral, safety, and pharmacokinetic properties. The clinical evaluation of beclabuvir in combination with both the NS5A replication complex inhibitor daclatasvir and the NS3 protease inhibitor asunaprevir in a single, fixed-dose formulation (Ximency) resulted in the approval by the Japanese Pharmaceutical and Food Safety Bureau for its use in the treatment of patients infected with genotype 1 HCV.