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.
Subject(s)
Anilides/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Propionates/chemical synthesis , Protein Kinase Inhibitors , Anilides/chemistry , Anilides/pharmacology , Animals , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Fibroblasts/drug effects , Fibroblasts/enzymology , Humans , Inhibitory Concentration 50 , Propionates/chemistry , Propionates/pharmacology , Protein Kinases/metabolism , Protein Serine-Threonine Kinases , Pyruvate Dehydrogenase Acetyl-Transferring Kinase , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Enzyme Inhibitors/pharmacology , Propionates/pharmacology , Protein Kinase Inhibitors , Protein Kinases , Amides , Animals , Area Under Curve , Biological Availability , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Humans , Lactic Acid/blood , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Inbred C57BL , Propionates/chemistry , Propionates/pharmacokinetics , Protein Serine-Threonine Kinases , Pyruvate Dehydrogenase Acetyl-Transferring Kinase , Rats , Rats, Sprague-DawleySubject(s)
Amides/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Propionates/chemical synthesis , Protein Kinase Inhibitors , Protein Kinases , Administration, Oral , Amides/chemistry , Amides/pharmacokinetics , Amides/pharmacology , Animals , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Fibroblasts , Humans , In Vitro Techniques , Lactic Acid/metabolism , Propionates/chemistry , Propionates/pharmacokinetics , Propionates/pharmacology , Protein Serine-Threonine Kinases , Pyruvate Dehydrogenase Acetyl-Transferring Kinase , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
SAH 51-641 (1) is a potent hypoglycemic agent, which acts by inhibiting hepatic gluconeogenesis. It is a prodrug of 4-(2, 2-dimethyl-1-oxopropyl)benzoic acid (2) and 4-(2, 2-dimethyl-1-hydroxypropyl)benzoic acid (3), which sequester coenzyme A (CoA) in the mitochondria, and inhibits medium-chain acyltransferase. 1-3 and 4-tert-butylbenzoic acid all cause testicular degeneration in rats at pharmacologically active doses. 14b (FOX 988) is a prodrug of 3, which is metabolized in the liver at a rate sufficient enough to have hypoglycemic potency (an ED50 of 65 micromol/kg, 28 mg/kg/day, for glucose lowering), yet by avoiding significant escape of the metabolite 3 to the systemic circulation, it avoids the testicular toxicity at doses up to 1500 micromol/kg/day. 14b was selected for clinical studies.
Subject(s)
Acetophenones/chemical synthesis , Benzoates/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Prodrugs/chemical synthesis , Acetophenones/chemistry , Acetophenones/pharmacology , Animals , Benzoates/blood , Benzoates/chemistry , Benzoates/pharmacology , Diabetes Mellitus, Experimental/drug therapy , Drug Evaluation, Preclinical , Fatty Acids/metabolism , Gluconeogenesis , Hypoglycemic Agents/blood , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , In Vitro Techniques , Liver/cytology , Liver/drug effects , Liver/metabolism , Male , Oxidation-Reduction , Prodrugs/chemistry , Prodrugs/pharmacology , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Testis/drug effects , Testis/metabolismABSTRACT
A series of substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones was synthesized from amino alcohols or amino thiols and keto acids. A pharmacological model based on the results obtained with these compounds led to the synthesis and evaluation of a series of isoxazoles and other monocyclic compounds. These were evaluated for their ability to enhance glucose utilization in cultured L6 myocytes. The in vivo hypoglycemic efficacy and potency of these compounds were evaluated in a model of type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus), the ob/ob mouse. 25a(2S) (SDZ PGU 693) was selected for further pharmacological studies.
