Molecular Mechanism by which a Potent Hepatitis C Virus NS3-NS4A Protease Inhibitor Overcomes Emergence of Resistance.
Boehringer Ingelheim (Canada) Ltd., Canada.Journal of Biological Chemistry (Impact Factor: 4.57). 12/2012; 288(8). DOI: 10.1074/jbc.M112.439455
Although optimizing the resistance profile of an inhibitor can be challenging, it is potentially important for improving the long term effectiveness of antiviral therapy. This work describes our rational approach towards the identification of a macrocyclic acyl sulfonamide that is a potent inhibitor of the NS3-NS4A proteases of all HCV genotypes, and of a panel of genotype 1 resistant variants. The enhanced potency of this compound versus variants D168V and R155K facilitated X-ray determination of the inhibitor-variant complexes. In turn, these structural studies revealed a complex molecular basis of resistance, and rationalized how such compounds are able to circumvent these mechanisms.
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ABSTRACT: Given the emergence of resistance observed for the current clinical-stage HCV NS3 protease inhibitors, there is a need for new inhibitors with a higher barrier to resistance. We recently reported our rational approach to the discovery of macrocyclic acylsulfonamides as HCV protease inhibitors addressing potency against clinically-relevant resistant variants. Using X-ray crystallography of HCV protease variant/inhibitor complexes, we shed light on the complex structural mechanisms by which the D168V and R155K residue mutations confer resistance to NS3 protease inhibitors. Here, we disclose SAR investigation and ADME/PK optimization leading to the identification of inhibitors with significantly improved potency against the key resistant variants and with increased liver partitioning.Journal of Medicinal Chemistry 03/2013; 57(5). DOI:10.1021/jm400121t · 5.45 Impact Factor
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ABSTRACT: The stereoselective synthesis of novel multifunctionalized cyclopropanes from gamma,delta-epoxy malonates and amines mediated by LiCl under mild conditions was carried out. This domino reaction involves the initial cyclopropanation via intramolecular ring-opening of gamma,delta-epoxy malonates through the cooperative catalysis of LiCl (acting as a Lewis acid) and a Bronsted base (a primary or, in selected cases, a secondary amine). The sequential events consisted of lactonization and aminolysis of the lactone ring that ultimately furnished cyclopropane carboxamides with different substitution patterns in good isolated yields. In all cases, a quaternary stereogenic center could be perfectly assembled with a single diastereoisomer being obtained. This method proceeds with high atom economy, is remarkably modular, operationally simple and tolerates a variety of functional groups. The involvement of readily available starting materials, the broad scope, and the use of a sustainable solvent (methanol or ethanol) at ambient temperature make this domino process highly effective. A reaction mechanism is proposed based on the experimental observations involving the preparation and reactivity of cyclopropylidene lactones as possible intermediates of the domino process.The Journal of Organic Chemistry 04/2014; 79(10). DOI:10.1021/jo500712t · 4.72 Impact Factor
- RSC Drug Discovery Series 01/2015; 2015(40):235-282.
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