Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes.

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.

NMR identification of an S-linked glucuronide of a triazole thione formed in vitro.

The metabolism of 3-([3-(2-Chlorophenyl)-4,5-dihydro-5-thioxo-1H-1,2,4-triazol-1-yl]methyl)benzonitrile (AR-C133611XX) was studied in isolated dog hepatocytes. The major metabolite of AR-C133611XX was characterized by high performance liquid chromatography-mass spectrometry and NMR and found to be the product of direct glucuronidation. Evidence from 1H and 13C-NMR chemical shifts and a long-range proton carbon correlation experiment was used to deduce that glucuronidation had taken place on the sulfur atom.