Eric Jolicoeur

N-Acetamideindolecarboxylic acid allosteric ‘finger-loop’ inhibitors of the hepatitis C virus NS5B polymerase: discovery and initial optimization studies

SAR studies at the N(1)-position of allosteric indole-based HCV NS5B inhibitors has led to the discovery of acetamide derivatives with good cellular potency in subgenomic replicons (EC(50) <200 nM). This class of inhibitors displayed improved physicochemical properties and favorable ADME-PK profiles over previously described analogs in this class.

From benzimidazole to indole-5-carboxamide Thumb Pocket I inhibitors of HCV NS5B polymerase. Part 1: Indole C-2 SAR and discovery of diamide derivatives with nanomolar potency in cell-based subgenomic replicons

Replacement of the benzimidazole core of allosteric Thumb Pocket 1 HCV NS5B finger loop inhibitors by more lipophilic indole derivatives provided up to 30-fold potency improvements in cell-based subgenomic replicon assays. Optimization of C-2 substitution on the indole core led to the identification of analogs with EC(50)<100 nM and modulated the pharmacokinetic properties of the inhibitors based on preliminary data from in vitro ADME profiles and in vivo rat PK.

Generation of glycinyl radicals via a 1,5-hydrogen atom transfer reaction. Applications to γ-lactam formation

Abstract Glycinyl radicals can be generated using a simple protecting/radical translocating group and used in the preferential formation of trans -3,4-disubstituted γ-lactams via a radical cyclisation reaction.

Indole 5-carboxamide Thumb Pocket I inhibitors of HCV NS5B polymerase with nanomolar potency in cell-based subgenomic replicons (part 2): Central amino acid linker and right-hand-side SAR studies

In this part 2, new indole 5-carboxamide Thumb Pocket 1 inhibitors of HCV NS5B polymerase are described. Structure-activity relationships (SAR) were explored at the central amino acid linker position and the right-hand-side of the molecule in an attempt to identify molecules with a balanced overall profile of potency (EC(50)<100 nM), physicochemical properties and ADME characteristics.

Synthesis and optimization of a novel series of HCV NS3 protease inhibitors: 4-Arylproline analogs

In this report we describe the synthesis and evaluation of diverse 4-arylproline analogs as HCV NS3 protease inhibitors. Introduction of this novel P2 moiety opened up new SAR and, in combination with a synthetic approach providing a versatile handle, allowed for efficient exploitation of this novel series of NS3 protease inhibitors. Multiple structural modifications of the aryl group at the 4-proline, guided by structural analysis, led to the identification of analogs which were very potent in both enzymatic and cell based assays. The impact of this systematic SAR on different drug properties is reported.