title: Anilides of (R)-trifluoro-2-hydroxy-2-methylpropionic acid as inhibitors of pyruvate dehydrogenase kinase.
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 (IC(50) = 35 +/- 1.4 microM). 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 IC(50) of 13 +/- 1.5 nM, enhances the oxidation of [(14)C]lactate into (14)CO(2) in human fibroblasts, lowers blood lactate levels significantly 2.5 and 5 h after oral doses as low as 30 micromol/kg, and increases the ex vivo activity of PDH in muscle, kidney, liver, and heart tissues. However, in contrast to sodium dichloroacetate (DCA), these PDHK inhibitors did not lower blood glucose levels. Nevertheless, they are effective at increasing the utilization and disposal of lactate and could be of utility to ameliorate conditions of inappropriate blood lactate elevation.
authors.affiliation: Metabolic and Cardiovascular Disease Research, Novartis Institute for Biomedical Research, Summit, New Jersey 07901, USA. greg.bebernitz@pharma.novartis.com
authors.forename: G R
authors.initials: GR
authors.lastname: Bebernitz
authors.forename: T D
authors.initials: TD
authors.lastname: Aicher
authors.forename: J L
authors.initials: JL
authors.lastname: Stanton
authors.forename: J
authors.initials: J
authors.lastname: Gao
authors.forename: S S
authors.initials: SS
authors.lastname: Shetty
authors.forename: D C
authors.initials: DC
authors.lastname: Knorr
authors.forename: R J
authors.initials: RJ
authors.lastname: Strohschein
authors.forename: J
authors.initials: J
authors.lastname: Tan
authors.forename: L J
authors.initials: LJ
authors.lastname: Brand
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.forename: W H
authors.initials: WH
authors.lastname: Wang
authors.forename: C C
authors.initials: CC
authors.lastname: Vinluan
authors.forename: E L
authors.initials: EL
authors.lastname: Kaplan
authors.forename: C J
authors.initials: CJ
authors.lastname: Dragland
authors.forename: D
authors.initials: D
authors.lastname: DelGrande
authors.forename: A
authors.initials: A
authors.lastname: Islam
authors.forename: R J
authors.initials: RJ
authors.lastname: Lozito
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.forename: W M
authors.initials: WM
authors.lastname: Maniara
authors.forename: W R
authors.initials: WR
authors.lastname: Mann
mesh_terms: D000813:Anilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000813:Anilides; D004791:Enzyme Inhibitors; D011422:Propionates; D047428:Protein Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases