Thomas Daniel Aicher

Non-charged thiamine analogs as inhibitors of enzyme transketolase.

Inhibition of the thiamine-utilizing enzyme transketolase (TK) has been linked with diminished tumor cell proliferation. Most thiamine antagonists have a permanent positive charge on the B-ring, and it has been suggested that this charge is required for diphosphorylation by thiamine pyrophosphokinase (TPPK) and binding to TK. We sought to make neutral thiazolium replacements that would be substrates for TPPK, while not necessarily needing thiamine transporters (ThTr1 and ThTr2) for cell penetration. The synthesis, SAR, and structure-based rationale for highly potent non-thiazolium TK antagonists are presented.

Triterpene and diterpene inhibitors of pyruvate dehydrogenase kinase (PDK).

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.

Novel acyl coenzyme A (CoA): diacylglycerol acyltransferase-1 inhibitors: synthesis and biological activities of diacylethylenediamine derivatives.

A series of diacylethylenediamine derivatives were synthesized and evaluated for their inhibitory activity against DGAT-1 and pharmacokinetic profile to discover new small molecule DGAT-1 inhibitors. Among the compounds, N-[2-({[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)ethyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 3x showed potent inhibitory activity and excellent PK profile. Oral administration of 3x to mice with dietary-induced obesity resulted in reduced body weight gain and white adipose tissue weight.

Diverse mechanisms of inhibition of pyruvate dehydrogenase kinase by structurally distinct inhibitors.

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.

Identification of a New Class of Glucokinase Activators through Structure-Based Design.

Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high glucose concentrations. Glucose flux through GK also contributes to reducing hepatic glucose output. Because many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, compounds that can activate GK may serve as effective treatments for type 2 diabetes. Herein we report the identification and initial optimization of a novel series of allosteric glucokinase activators (GKAs). We discovered an initial thiazolylamino pyridine-based hit that was optimized using a structure-based design strategy and identified 26 as an early lead. Compound 26 demonstrated a good balance of in vitro potency and enzyme kinetic parameters and demonstrated blood glucose reductions in oral glucose tolerance tests in both C57BL/6J mice and high-fat fed Zucker diabetic fatty rats.

Novel therapeutics and targets for the treatment of diabetes.

The microvascular complications of insufficiently controlled diabetes (neuropathy, retinopathy and nephropathy) and the marked increased risk of macrovascular events (e.g., stroke and myocardial infarction) have a dire impact on society in both human and economic terms. In Type 1 diabetes total β-cell loss occurs. In Type 2 diabetes, partial β-cell loss occurs before diagnosis, and the progressive β-cell loss during the life of the patient increases the severity of the disease. In patients with diabetes, increased insulin resistance in the muscle and liver are key pathophysiologic defects. In addition, defects in metabolic processes in the fat, GI tract, brain, pancreatic α-cells and kidney are detrimental to the overall health of the patient. This review addresses novel therapies for these deficiencies in clinical and preclinical evaluation, emphasizing their potential to address glucose homeostasis, β-cell mass and function, and the comorbidities of cardiovascular disease and obesity.

A novel coenzyme A:diacylglycerol acyltransferase 1 inhibitor stimulates lipid metabolism in muscle and lowers weight in animal models of obesity.

Obesity is characterized by the accumulation of triacylglycerol in adipocytes. Coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) is one of two known DGAT enzymes that catalyze the final and only committed step in triacylglycerol synthesis. In this report, we describe the pharmacological effects of a novel selective DGAT1 inhibitor, Compound-A. This compound inhibited triacylglycerol synthesis in both adipocytes and skeletal myotubes, and increased fatty acid oxidation in skeletal myotubes at 1 μM. The repeated administration of Compound-A to diet-induced obese C57BL/6J and genetically obese KKA(y) mice (3-30 mg/kg for 3-4 weeks) significantly decreased the visceral fat pad weights and the hepatic lipid contents compared to controls without affecting food intake. In addition, fatty acid oxidation in skeletal muscle tissues was increased by the treatment of Compound-A in both mice strains. This is the first report demonstrating that a small synthetic DGAT1 inhibitor increases fatty acid oxidation in skeletal muscle in vitro and ex vivo. These results suggest that DGAT1 inhibition is a promising therapeutic approach for the treatment of obesity and lipid abnormalities such as hepatic steatosis.

Synthesis of chiral tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones☆

Abstract In our investigations of potential hypoglycemic agents,2 it was desired to evaluate optically pure tetrahydropyrrolo[2,1-β]thiazol-5-ones. A novel, practical synthesis of each enantiomer of 1 via formation, separation, and hydrolysis of diastereomeric amidine derivatives is described.

Discovery of 2-pyridylureas as glucokinase activators.

Glucokinase (GK) is the rate-limiting step for insulin release from the pancreas in response to high levels of glucose. Flux through GK also contributes to reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can allosterically activate GK may address this issue. Herein we report the identification and initial optimization of a novel series of glucokinase activators (GKAs). Optimization led to the identification of 33 as a compound that displayed activity in an oral glucose tolerance test (OGTT) in normal and diabetic mice.

Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394

Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure-activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes.