Anilides of (R)-trifluoro-2-hydroxy-2-methylpropionic acid as inhibitors of pyruvate dehydrogenase kinase.

TLDR: Small electron-withdrawing groups on the ortho position of the anilide increased potency 20-40-fold and could be of utility to ameliorate conditions of inappropriate blood lactate elevation.

Abstract: The optimization of a series of anilide derivatives of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid as inhibitors of pyruvate dehydrogenase kinase (PDHK) is described that started from N-phenyl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide 1 (IC50 = 35 ± 1.4 μM). It was found that small electron-withdrawing groups on the ortho position of the anilide, i.e., chloro, acetyl, or bromo, increased potency 20−40-fold. The oral bioavailability of the compounds in this series is optimal (as measured by AUC) when the anilide is substituted at the 4-position with an electron-withdrawing group (i.e., carboxyl, carboxyamide, and sulfoxyamide). N-(2-Chloro-4-isobutylsulfamoylphenyl)-(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide (10a) inhibits PDHK in the primary enzymatic assay with an IC50 of 13 ± 1.5 nM, enhances the oxidation of [14C]lactate into 14CO2 in human fibroblasts, lowers blood lactate levels significantly 2.5 and 5 h after oral doses as low as 30 μmol/kg, and increases the ex vivo activity of...