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Improving Metabolic Stability with Deuterium: The Discovery of BMT-052, a Pan-genotypic HCV NS5B Polymerase Inhibitor

Kyle Parcella, Kyle J. Eastman, Kap‐Sun Yeung, Katharine Grant-Young, Juliang Zhu, Tao Wang, Zhongxing Zhang, Zhiwei Yin, Dawn D. Parker, Kathy Mosure,

ACS Medicinal Chemistry Letters · 2017 · 26 citations · 8 references

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Concepts

PharmacyMedicinal ChemistryPharmacologyDrug DiscoveryMetabolic StabilityMetabolismAntiviral TherapyEnzyme InhibitionMetabolic Stability EnhancementMetabolic Stability OptimizationPolymerase Chain ReactionStructure-metabolism RelationshipsDrug Candidate OptimizationMetabolic Soft Spot OptimizationMetabolic Stability ModulationStructure - Metabolism Relationship Analysis

Abstract

Iterative structure–activity analyses in a class of highly functionalized furo[2,3- b ]pyridines led to the identification of the second generation pan-genotypic hepatitis C virus NS5B polymerase primer grip inhibitor BMT-052 ( 14 ), a potential clinical candidate. The key challenge of poor metabolic stability was overcome by strategic incorporation of deuterium at potential metabolic soft spots. The preclinical profile and status of BMT-052 ( 14 ) is described.