AZD-7687

We have developed a novel mechanistic pharmacokinetic‐pharmacodynamic (PK/PD) model to describe the time course of plasma triglyceride (TAG) after Oral Lipid Tolerance Test (OLTT) and the effects of AZD7687, an inhibitor of diacylglycerol acyltransferase 1 (DGAT1), in humans, rats, and mice. Pharmacokinetic and plasma TAG data were obtained both in animals and in two phase I OLTT studies. In the PK/PD model, the introduction of exogenous TAG is represented by a first order process. The endogenous production and removal of TAG from plasma are described with a turnover model. AZD7687 inhibits the contribution of exogenous TAG into circulation. One or two compartment models with first order absorption was used to describe the PK of AZD7687 for the different species. Nonlinear mixed effect modeling was used to fit the model to the data. The effects of AZD7687 on the plasma TAG time course during an OLTT as well as interindividual variability were well described by the model in all three species. Meal fat content or data from single vs repeated dosing did not affect model parameter estimates. Body mass index was found to be a significant covariate on the plasma TAG baseline. The system parameters of the model will facilitate analysis for other compounds and provide tools to bring the standard of OLTT data analysis closer to the analyses of Oral Glucose Tolerance Test data maximizing knowledge gain.

Diacylglycerol acyltransferase (DGAT), the only limited enzyme in the synthesis of triacylglycerol (TAG), is regarded as an important therapeutic target for human obesity and other metabolic syndromes.Compounds 5-7 and 8 (I) were designed and synthesized, in which the lactone group of aphadilactone C was introduced into the PF-04620110 and AZD-7687, which have entered into the clin. research, to verify whether the lactone in aphadilactone C played the same role as carboxylic group in PF-04620110 and AZD-7687.The final vitro assay showed that compounds 5-8 have not the inhibition activity to DGAT1.This might suggest that inhibition mechanism of aphadilactone C was not the same as PF-04620110 and AZD-7687.