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

The optimization of a series of anilide derivatives of (R)-3,3,3-trifluoro- 2-hydroxy-2-methylpropionic acid as inhibitors of pyruvate dehydrogenase ki nase (PDHK) is described that started from N-phenyl-3,3,3-trifluoro-2-hydro xy-2-methylpropanamid 1 (IC50 = 35 +/- 1.4 mu M). It was found that small e lectron-withdrawing groups on the ortho position of the anilide, i.e., chlo ro, acetyl, or bromo, increased potency 20-40-fold. The oral bioavailabilit y 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-isobutylsu lfamoylphenyl)-(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide (10a) inh ibits PDHK in the primary enzymatic assay with an IC50 Of 13 +/- 1.5 nM, en hances the oxidation of [C-14]lactate into (CO2)-C-14 in human fibroblasts, lowers blood lactate levels significantly 2.5 and 5 h after oral doses as low as 30 mu mol/kg, and increases the ex vivo activity of PDH in muscle, k idney, liver, and heart tissues. However, in contrast to sodium dichloroace tate (DCA), these PDHK inhibitors did not lower blood glucose levels. Never theless, they are effective at increasing the utilization and disposal of l actate and could be of utility to ameliorate conditions of inappropriate bl ood lactate elevation.