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1.
Biochim Biophys Acta ; 1480(1-2): 283-92, 2000 Jul 14.
Article in English | MEDLINE | ID: mdl-11004568

ABSTRACT

The mechanism of action of structurally distinct pyruvate dehydrogenase kinase (PDK) inhibitors was examined in assays with experimental contexts ranging from an intact pyruvate dehydrogenase complex (PDC) with and without supplemental ATP or ADP to a synthetic peptide substrate to PDK autophosphorylation. Some compounds directly inhibited the catalytic activity of PDKs. Some of the inhibitor classes tested inhibited autophosphorylation of recombinant PDK1 and PDK2. During these studies, PDC was shown to be directly inhibited by a novel mechanism; the addition of supplemental recombinant PDKs, an effect that is ADP-dependent and partly alleviated by members of each of the compound classes tested. Overall, these data demonstrate that small molecules acting at diverse sites can inhibit PDK activity.


Subject(s)
Enzyme Inhibitors/pharmacology , Protein Kinase Inhibitors , Protein Kinases , Electrophoresis, Polyacrylamide Gel , Enzyme Inhibitors/chemistry , Molecular Structure , Phosphorylation , Protein Serine-Threonine Kinases , Pyruvate Dehydrogenase Acetyl-Transferring Kinase
2.
J Med Chem ; 43(11): 2248-57, 2000 Jun 01.
Article in English | MEDLINE | ID: mdl-10841803

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 Relationship
3.
J Med Chem ; 43(2): 236-49, 2000 Jan 27.
Article in English | MEDLINE | ID: mdl-10649979

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.


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-Dawley
4.
Bioorg Med Chem Lett ; 9(15): 2223-8, 1999 Aug 02.
Article in English | MEDLINE | ID: mdl-10465550

ABSTRACT

Several oximes of triterpenes with a 17-beta hydroxyl and abietane derivatives are inhibitors of pyruvate dehydrogenase kinase (PDK) activity. The oxime 12 and dehydroabietyl amine 2 exhibit a blood glucose lowering effect in the diabetic ob/ob mouse after a single oral dose of 100 micromol/kg. However, the mechanism of the blood glucose lowering effect is likely unrelated to PDK inhibition.


Subject(s)
Diterpenes/chemical synthesis , Protein Kinase Inhibitors , Protein Kinases , Triterpenes/chemical synthesis , Administration, Oral , Animals , Blood Glucose/drug effects , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Disease Models, Animal , Diterpenes/pharmacology , Diterpenes/therapeutic use , Mice , Protein Serine-Threonine Kinases , Pyruvate Dehydrogenase Acetyl-Transferring Kinase , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Triterpenes/pharmacology , Triterpenes/therapeutic use
6.
J Med Chem ; 42(1): 153-63, 1999 Jan 14.
Article in English | MEDLINE | ID: mdl-9888840

ABSTRACT

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/metabolism
7.
J Med Chem ; 41(23): 4556-66, 1998 Nov 05.
Article in English | MEDLINE | ID: mdl-9804695

ABSTRACT

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.


Subject(s)
Hypoglycemic Agents/chemical synthesis , Oxazoles/chemical synthesis , Pyrroles/chemical synthesis , Thiazoles/chemical synthesis , Animals , Cell Line , Diabetes Mellitus, Type 2/drug therapy , Drug Evaluation, Preclinical , Glucose/metabolism , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Male , Mice , Mice, Inbred C57BL , Muscles/cytology , Oxazoles/chemistry , Oxazoles/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Rats , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacology
8.
Biochem J ; 334 ( Pt 3): 703-11, 1998 Sep 15.
Article in English | MEDLINE | ID: mdl-9729480

ABSTRACT

The activity of the pyruvate dehydrogenase multienzyme complex (PDC), which catalyses the oxidation of pyruvate to acetyl-CoA within the mitochondrion, is diminished in animal models of diabetes. Studies with purified PDC components have suggested that the kinases responsible for inactivating the decarboxylase catalytic subunits of the complex are most efficient in their regulatory role when they are bound to dihydrolipoyl acetyltransferase (E2) subunits, which form the structural core of the complex. We report that the addition of an exogenous E2 subdomain (inner lipoyl domain) to an intact PDC inhibits ATP-dependent inactivation of the complex. By combining molecular modelling, site-directed mutagenesis and biophysical characterizations, we have also identified two amino acid residues in this subdomain (Ile229 and Phe231) that largely determine the magnitude of this effect.


Subject(s)
Acetyltransferases/chemistry , Acetyltransferases/metabolism , Adenosine Triphosphate/metabolism , Pyruvate Dehydrogenase Complex/antagonists & inhibitors , Acetyltransferases/genetics , Animals , Catalytic Domain/genetics , Cloning, Molecular , Dihydrolipoyllysine-Residue Acetyltransferase , Humans , In Vitro Techniques , Models, Molecular , Mutagenesis, Site-Directed , Peptides/chemistry , Peptides/metabolism , Phosphorylation , Protein Conformation , Pyruvate Dehydrogenase Complex/chemistry , Pyruvate Dehydrogenase Complex/genetics , Rats , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Swine
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