ABSTRACT
A series of trifluoroacetophenone derivatives were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Some of the 'reverse amide' analogs were found to be potent inhibitors of MCD enzyme activity. The trifluoroacetyl group may interact with the MCD active site as the hydrate in a similar fashion to the hexafluoroisopropanol analogs reported previously. Adding electron-withdrawing groups to the phenyl ring stabilizes the hydrated species and enhances this interaction.
Subject(s)
Acetophenones/chemical synthesis , Acetophenones/pharmacology , Carboxy-Lyases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Indicators and Reagents , Malonyl Coenzyme A/metabolism , Propanols/chemistry , Structure-Activity RelationshipABSTRACT
Discovery of 5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamides as a new class of malonyl-coenzyme A decarboxylase (MCD) inhibitors is described. tert-Butyl 3-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamido)butanoate (5, CBM-301940) exhibited excellent potency and in vivo PK/ADME properties. It is the most powerful stimulant of glucose oxidation reported to date in isolated working rat hearts. Compound 5 improved the cardiac efficiency and function in a rat heart global ischemia/reperfusion model, suggesting MCD inhibitors may be useful for the treatment of ischemic heart diseases.
Subject(s)
Carboxy-Lyases/antagonists & inhibitors , Cardiotonic Agents/chemical synthesis , Isoxazoles/chemical synthesis , Administration, Oral , Animals , Biological Availability , Cardiotonic Agents/pharmacokinetics , Cardiotonic Agents/pharmacology , Crystallography, X-Ray , Isoxazoles/pharmacokinetics , Isoxazoles/pharmacology , Molecular Conformation , Myocardial Ischemia/drug therapy , Myocardial Ischemia/physiopathology , Myocardial Reperfusion , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of heteroaryl-substituted bis-trifluoromethyl carbinols were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Some thiazole-based derivatives showed potent in vitro MCD inhibitory activities and significantly increased glucose oxidation rates in isolated working rat hearts.
Subject(s)
Carboxy-Lyases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds/chemistry , Methanol/chemical synthesis , Methanol/pharmacology , Animals , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Glucose/chemistry , Glucose/metabolism , Heart/drug effects , In Vitro Techniques , Methanol/analogs & derivatives , Molecular Structure , Oxidation-Reduction , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The discovery and structure-activity relationship of first-generation small-molecule malonyl-CoA decarboxylase (MCD; CoA = coenzyme A) inhibitors are reported. We demonstrated that MCD inhibitors increased malonyl-CoA concentration in the isolated working rat hearts. Malonyl-CoA is a potent, endogenous, and allosteric inhibitor of carnitine palmitoyltransferase-I (CPT-I), a key enzyme for mitochondrial fatty acid oxidation. As a result of the increase in malonyl-CoA levels, fatty acid oxidation rates were decreased and the glucose oxidation rates were significantly increased. Demonstration of in vivo efficacy of methyl 5-(N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)morpholine-4-carboxamido)pentanoate (6u) in a pig ischemia model indicated that MCD inhibitors may be useful for treating ischemic heart diseases.
Subject(s)
Carboxy-Lyases/antagonists & inhibitors , Morpholines/chemical synthesis , Phenylurea Compounds/chemical synthesis , Animals , Energy Metabolism/drug effects , Fatty Acids/metabolism , Glucose/metabolism , In Vitro Techniques , Male , Malonyl Coenzyme A/metabolism , Morpholines/chemistry , Morpholines/pharmacology , Myocardial Ischemia/drug therapy , Myocardium/enzymology , Myocardium/metabolism , Oxidation-Reduction , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , SwineABSTRACT
We have previously reported the discovery of small molecule inhibitors of malonyl-CoA decarboxylase (MCD) as novel metabolic modulators, which inhibited fatty acid oxidation and consequently increased the glucose oxidation rates in the isolated working rat hearts. MCD inhibitors were also shown to improve cardiac efficiency in rat and pig demand-induced ischemic models through the mechanism-based modulation of energy metabolism. Herein, we describe the design and synthesis of a series of novel heterocyclic MCD inhibitors with a preference for substituted imidazole and isoxazole.
Subject(s)
Carboxy-Lyases/antagonists & inhibitors , Cardiotonic Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Animals , Cardiotonic Agents/pharmacology , Drug Design , Energy Metabolism , Enzyme Inhibitors/pharmacology , Fatty Acids/metabolism , Glucose/metabolism , Imidazoles/chemistry , Models, Chemical , Myocardial Ischemia/drug therapy , Myocardial Ischemia/metabolism , Oxidation-Reduction , Rats , SwineABSTRACT
A high performance liquid chromatographic method was developed that separated organic acids using the polar organic mode. The separation was obtained using a beta-cyclodextrin stationary phase with a mobile phase that was composed of acetonitrile/methanol/triethylamine (TEA)/acetic acid. The compounds were eluted under gradient conditions and the elution order depended on the number, type and position of the hydrogen bonding functional groups present in the molecule. Adjusting the acid to base ratio resulted in the biggest change in selectivity. In addition, increasing the methanol concentration decreased the retention times of the analytes, which had little effect on the selectivity. Using a certain set of conditions one could separate a large number of organic acids, which allowed these acids to be detected by UV and mass spectrometry. These conditions were used to evaluate the purity of potential pharmaceutical drug candidates that showed activity towards a kinase target vascular endothieal growth factor (Vegf). Each compound contained a carboxylic acid group that was critical to the activity. The method was able to give purity estimates of these samples, which were difficult to determine by other HPLC methods.
Subject(s)
Acids/chemistry , Drug Design , Organic Chemicals/chemistry , beta-Cyclodextrins/chemistry , Chromatography, High Pressure Liquid , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, UltravioletABSTRACT
The discovery and structure-activity relationship of a novel series of coumarin-based TNF-alpha inhibitors is described. Starting from the initial lead 1a, various derivatives were prepared surrounding the coumarin core structure to optimize the in vitro inhibitory activity of TNF-alpha production by human peripheral blood mononuclear cells (hPBMC), stimulated by bacterial lipopolysaccharide (LPS). Selected compounds also demonstrated in vivo inhibition of TNF-alpha production in rats.
Subject(s)
Coumarins/chemical synthesis , Coumarins/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Cells, Cultured , Dose-Response Relationship, Drug , Humans , Inhibitory Concentration 50 , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides/pharmacology , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Abnormally high rates of fatty acid oxidation and low rates of glucose oxidation are important contributors to the severity of ischemic heart disease. Malonyl coenzyme A (CoA) regulates fatty acid oxidation by inhibiting mitochondrial uptake of fatty acids. Malonyl CoA decarboxylase (MCD) is involved in the decarboxylation of malonyl CoA to acetyl CoA. Therefore, inhibition of MCD may decrease fatty acid oxidation and protect the ischemic heart, secondary to increasing malonyl CoA levels. Ex vivo working rat hearts aerobically perfused in the presence of newly developed MCD inhibitors showed an increase in malonyl CoA levels, which was accompanied by both a significant decrease in fatty acid oxidation rates and an increase in glucose oxidation rates compared with controls. Using a model of demand-induced ischemia in pigs, MCD inhibition significantly increased glucose oxidation rates and reduced lactate production compared with vehicle-treated hearts, which was accompanied by a significant increase in cardiac work compared with controls. In a more severe rat heart global ischemia/reperfusion model, glucose oxidation was significantly increased and cardiac function was significantly improved during reperfusion in hearts treated with the MCD inhibitor compared with controls. Together, our data show that MCD inhibitors, which increase myocardial malonyl CoA levels, decrease fatty acid oxidation and accelerate glucose oxidation in both ex vivo rat hearts and in vivo pig hearts. This switch in energy substrate preference improves cardiac function during and after ischemia, suggesting that pharmacological inhibition of MCD may be a novel approach to treating ischemic heart disease.
Subject(s)
Carboxy-Lyases/antagonists & inhibitors , Cardiotonic Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Fatty Acids/metabolism , Glucose/metabolism , Myocardial Ischemia/drug therapy , Myocardium/metabolism , Acetyl Coenzyme A , Animals , Cardiotonic Agents/pharmacology , Energy Metabolism , Enzyme Inhibitors/pharmacology , Esters/metabolism , Glycolysis , Malonyl Coenzyme A/metabolism , Mitochondria, Heart/drug effects , Mitochondria, Heart/metabolism , Models, Animal , Myocardial Ischemia/metabolism , Oxidation-Reduction , Rats , Rats, Sprague-Dawley , SwineABSTRACT
A novel series of chromene-based TNF-alpha inhibitors is described. These chromene derivatives inhibit bacterial lipopolysaccharide (LPS) stimulated production of TNF-alpha from human peripheral blood mononuclear cells (PBMC). Additionally, these compounds inhibit NF-kB mediated transcription activation.
