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

Iterative structure-activity analyses in a class of highly functionalized furo[2,3-]pyridines led to the identification of the second generation pan-genotypic hepatitis C virus NS5B polymerase primer grip inhibitor BMT-052 (), 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 () is described.

The discovery of a pan-genotypic, primer grip inhibitor of HCV NS5B polymerase.

The development of a series of novel 7-azabenzofurans exhibiting pan-genotype inhibition of HCV NS5B polymerase binding to the primer grip site is presented. Many challenges, including poor oral bioavailability, high clearance, bioactivation, high human serum shift, and metabolic stability were encountered and overcome through SAR studies. This work culminated in the selection of BMS-986139 () as a preclinical candidate.

Differentially functionalized diamines as novel ligands for the NPY2 receptor.

The synthesis of novel ligands for the NPY(2) receptor using solid phase split pool methodology is described. One of the analogues, diamine 16, was found to be a potent NPY(2) binder.

Identification of a potent and selective 5-HT(6) antagonist: one-step synthesis of (E)-3-(benzenesulfonyl)-2- (methylsulfanyl)pyrido[1,2-a]pyrimidin-4-ylidenamine from 2-(benzenesulfonyl)-3,3-bis(methylsulfanyl)acrylonitrile.

(E)-3-(Benzenesulfonyl)-2-(methylsulfanyl)pyrido[1,2-a]pyrimidin-4-ylidenamine (7) was found to be a potent and selective 5-HT(6) antagonist. A one-step synthesis of this compound is described.

Structure-activity relationships for a series of thiobenzamide influenza fusion inhibitors derived from 1,3,3-trimethyl-5-hydroxy-cyclohexylmethylamine.

The anti-influenza activity of a series of thiobenzamide fusion inhibitors derived from 1,3,3-trimethyl-5-hydroxy-cyclohexylmethylamine is profiled. Axial disposition of the thioamide moiety is essential for potent influenza inhibitory activity.