Molecular Mechanism by which a Potent Hepatitis C Virus NS3-NS4A Protease Inhibitor Overcomes Emergence of Resistance.
ABSTRACT 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 · 5.48 Impact Factor