title: Secondary amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid as inhibitors of pyruvate dehydrogenase kinase.
abstract: N'-methyl-N-(4-tert-butyl-1,2,5,6-tetrahydropyridine)thiourea, SDZ048-619 (1), is a modest inhibitor (IC(50) = 180 microM) of pyruvate dehydrogenase kinase (PDHK). In an optimization of the N-methylcarbothioamide moiety of 1, it was discovered that amides with a small acyl group, in particular appropriately substituted amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, are inhibitors of PDHK. Utilizing this acyl moiety, herein is reported the rationale leading to the optimization of a series of acylated piperazine derivatives. Methyl substitution of the piperazine at the 2- and 5-positions (with S and R absolute stereochemistry) markedly increased the potency of the lead compound (>1,000-fold). Oral bioavailability of the compounds in this series is good and is optimal (as measured by AUC) when the 4-position of the piperazine is substituted with an electron-poor benzoyl moiety. (+)-1-N-[2,5-(S, R)-Dimethyl-4-N-(4-cyanobenzoyl)piperazine]-(R)-3,3, 3-trifluoro-2-hydroxy-2-methylpropanamide (14e) inhibits PDHK in the primary enzymatic assay with an IC(50) of 16 +/- 2 nM, enhances the oxidation of [(14)C]lactate into (14)CO(2) in human fibroblasts with an EC(50) of 57 +/- 13 nM, diminishes lactate significantly 2.5 h post-oral-dose at doses as low as 1 micromol/kg, and increases the ex vivo activity of PDH in muscle, liver, and fat tissues in normal Sprague-Dawley rats. These PDHK inhibitors, however, do not lower glucose in diabetic animal models.
authors.affiliation: Novartis Institute for Biomedical Research, 556 Morris Avenue, Summit, New Jersey 07901, USA. Thomas.Aicher@pharma.novartis.com
authors.forename: T D
authors.initials: TD
authors.lastname: Aicher
authors.forename: R C
authors.initials: RC
authors.lastname: Anderson
authors.forename: J
authors.initials: J
authors.lastname: Gao
authors.forename: S S
authors.initials: SS
authors.lastname: Shetty
authors.forename: G M
authors.initials: GM
authors.lastname: Coppola
authors.forename: J L
authors.initials: JL
authors.lastname: Stanton
authors.forename: D C
authors.initials: DC
authors.lastname: Knorr
authors.forename: D M
authors.initials: DM
authors.lastname: Sperbeck
authors.forename: L J
authors.initials: LJ
authors.lastname: Brand
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: H C
authors.initials: HC
authors.lastname: Tomaselli
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 S
authors.initials: WS
authors.lastname: Fillers
authors.forename: D
authors.initials: D
authors.lastname: DelGrande
authors.forename: R E
authors.initials: RE
authors.lastname: Walter
authors.forename: W R
authors.initials: WR
authors.lastname: Mann
mesh_terms: D000577:Amides; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D019344:Lactic Acid / Q000097:blood; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011422:Propionates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D011422:Propionates; D047428:Protein Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019344:Lactic Acid; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases