ABSTRACT
A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Oxadiazoles/chemical synthesis , Animals , Diabetes Mellitus/drug therapy , Diacylglycerol O-Acyltransferase/metabolism , Dogs , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Half-Life , High-Throughput Screening Assays , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Ligands , Mice , Obesity/drug therapy , Oxadiazoles/pharmacokinetics , Quantitative Structure-Activity Relationship , RatsABSTRACT
Inhibition of DGAT-1 is increasingly seen as an attractive mechanism with the potential for treatment of obesity and other elements of the metabolic syndrome. We report here a bicyclooctaneacetic acid derivative in the pyrimidinooxazine structural class of DGAT-1 inhibitors that has good potency, selectivity, and pharmacokinetic characteristics across a variety of species. This compound is an effective inhibitor of DGAT-1 in both intestinal and adipose tissue, which results in a reduction in body weight or body weight gain following oral administration in both mouse and rat models of dietary-induced obesity.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Oxazines/pharmacology , Pyrimidines/pharmacology , Administration, Oral , Animals , Body Weight/drug effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/therapeutic use , Female , Humans , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Inbred C57BL , Obesity/drug therapy , Rats , Rats, Wistar , Spectrometry, Mass, Electrospray IonizationABSTRACT
BACKGROUND: Mice that lack acyl CoA:diacylglycerol acyltransferase (Dgat1-/- mice) are reported to have a reduced body fat content and improved glucose tolerance and insulin sensitivity. Studies so far have focussed on male null mice fed a high fat diet and there are few data on heterozygotes. We compared male and female Dgat1-/-, Dgat1+/- and Dgat1+/+ C57Bl/6 mice fed on either standard chow or a high fat diet. RESULTS: Body fat content was lower in the Dgat1-/- than the Dgat1+/+ mice in both experiments; lean body mass was higher in male Dgat1-/- than Dgat1+/+ mice fed on the high fat diet. Energy intake and expenditure were higher in male Dgat1-/- than Dgat1+/+ mice; these differences were less marked or absent in females. The body fat content of female Dgat1+/- mice was intermediate between that of Dgat1-/- and Dgat1+/+ mice, whereas male Dgat1+/- mice were similar to or fatter than Dgat1+/+ mice. Glucose tolerance was improved and plasma insulin reduced in Dgat1-/- mice fed on the high fat diet, but not on the chow diet. Both male and female Dgat1+/- mice had similar glucose tolerance to Dgat1+/+ mice. CONCLUSION: These results suggest that although ablation of DGAT1 improves glucose tolerance by preventing obesity in mice fed on a high fat diet, it does not improve glucose tolerance in mice fed on a low fat diet.
