ABSTRACT
This article provides evidence of a new class of compounds, 1,3-diaryl-[1H]-pyrazole-4-acetamides, initially identified from their ability to increase glucose transport in an adipocyte and muscle cell line and ultimately demonstrating dramatic glucose lowering in ob/ob mice, a diabetic animal model. The lead compound, 1, possessed some behavioral-like effects which were removed by structural variation during the course of this investigation. Specifically, 11g (R1 = meta-CF(3), Ar2 = 4'biphenyl, R3 = diethylamide) illustrated the potency of this series with ED(50) values for glucose lowering in ob/ob mice of 3.0 mg/kg/day. Concomitant with its effect on glucose lowering, 11g also caused a 50% reduction in insulin levels consistent with an agent that increases whole body insulin sensitivity. 11g showed favorable pharmacokinetic data with acceptable absorption, negligible metabolism, and good duration of action. 11g demonstrated no appreciable adipogenic effect through PPAR gamma agonism, a characteristic of the thiazolidinediones (TZD), and so represents a potentially new class of agents for the treatment of diabetes.
Subject(s)
Acetamides/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Glucose/metabolism , Hypoglycemic Agents/pharmacology , Pyrazoles/pharmacology , Acetamides/chemical synthesis , Acetamides/chemistry , Acetamides/pharmacokinetics , Adipose Tissue/cytology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Behavior, Animal/drug effects , Biological Availability , Blood Glucose/analysis , Cell Line , Diabetes Mellitus/blood , Diabetes Mellitus/drug therapy , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Muscle, Skeletal/cytology , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The overproduction of glucose by the liver in NIDDM patients markedly contributes to their fasting hyperglycemia and is a direct consequence of the increased oxidation of excess free fatty acids (FFA) being released from the adipocyte. 2-(1,1-Dimethylethyl)-2-(4-methylphenyl)[1,3]dioxolane (SAH51-641, 1) has previously been demonstrated to reduce glucose levels in animal models of diabetes by reducing fatty acid oxidation and hence depriving the system of the energy and cofactors necessary for gluconeogenesis. However, attempts at lowering glucose levels in vivo with 1 have been associated with toxicity in other organs such as the testes. An approach was developed utilizing the natural processing of triglyceride-like intermediates as a basis for selectively targeting the absorption, processing, and delivery of a prodrug to the liver. Compounds were identified by this method which lowered glucose levels in vivo without releasing toxic amounts of the active metabolites of 1 into circulation.
Subject(s)
Benzoates/chemistry , Benzoates/chemical synthesis , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/chemical synthesis , Liver/drug effects , Prodrugs/chemical synthesis , Animals , Area Under Curve , Benzoates/adverse effects , Benzoates/pharmacology , Diabetes Mellitus, Experimental/blood , Fatty Acids/metabolism , Hepatocytes/metabolism , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , In Vitro Techniques , Liver/metabolism , Male , Oxidation-Reduction , Prodrugs/adverse effects , Prodrugs/chemistry , Prodrugs/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
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 RelationshipSubject(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.
