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

…, RJ Strohschein, J Tan, LJ Brand, C Liu…

Index: Bebernitz, Gregory R.; Aicher, Thomas D.; Stanton, James L.; Gao, Jiaping; Shetty, Suraj S.; Knorr, Douglas C.; Strohschein, Robert J.; Tan, Jennifer; Brand, Leonard J.; Liu, Charles; Wang, Wei H.; Vinluan, Christine C.; Kaplan, Emma L.; Dragland, Carol J.; DelGrande, Dominick; Islam, Amin; Lozito, Robert J.; Liu, Xilin; Maniara, Wieslawa M.; Mann, William R. Journal of Medicinal Chemistry, 2000 , vol. 43, # 11 p. 2248 - 2257

Full Text: HTML

Citation Number: 42

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, ie, chloro, acetyl, or bromo, increased potency 20-40-fold. The oral bioavailability of the ...