Diacylglycerol acyltransferases : potential roles as pharmacological targets

Triglyceride (TG) synthesis occurs in many cell-types, but only the adipocyte is specialised for TG storage. The increased incidence of obesity and its attendant pathologies have increased interest in pharmacological strategies aimed at inhibition of triglyceride synthesis. In the liver this would also appear to offer the advantages of the prevention of steatosis and/or dyslipidaemia. The two major enzymes that have DGAT activity appear to have specialised functions, that are most evident in triglyceride-secreting tissues. The presence of triglyceride in non-adipose cells can lead to (through lipolysis), or be a marker for, undesirable complications such as insulin resistance, or can be indicative of simultaneously high capacities for triglyceride synthesis, lipolysis and oxidation of fatty acids as in highly aerobic, trained muscle. Consequently, inhibition of triglyceride synthesis may not be a straightforward strategy, either in terms of its achievement pharmacologically or in its anticipated outcomes. The metabolic complexities of triglyceride synthesis, with particular reference to the diacylglycerol acyltransferases (DGATs) are considered in this short review

Discovery and optimization of efficacious neutral 4-amino-6-biphenyl-7,8-dihydropyrimido[5,4-f][1,4] oxazepin-5-one diacylglycerol acyl transferase-1 (DGAT1) inhibitors

Neutral DGAT1 inhibitors have been designed with comparable pre-clinical efficacy and PK/PD to those previously described for acidic inhibitors.</p

Optimisation of biphenyl acetic acid inhibitors of diacylglycerol acetyl transferase 1-the discovery of AZD2353

Focus on ligand efficiency, ligand lipophilicity efficiency, and conformational restriction led to the discovery of AZD2353.</p

Design and synthesis of a novel series of cyclohexyloxy-pyridyl derivatives as inhibitors of diacylglycerol acyl transferase 1

Design and synthesis of a novel series of cyclohexyloxy-pyridyl inhibitors of diacylglycerol acyl transferase 1.</p

Design and Optimization of Pyrazinecarboxamide-Based Inhibitors of Diacylglycerol Acyltransferase 1 (DGAT1) Leading to a Clinical Candidate Dimethylpyrazinecarboxamide Phenylcyclohexylacetic Acid (AZD7687)

A new series of pyrazinecarboxamide DGAT1 inhibitors was designed to address the need for a candidate drug with good potency, selectivity, and physical and DMPK properties combined with a low predicted dose in man. Rational design and optimization of this series led to the discovery of compound <b>30</b> (AZD7687), which met the project objectives for potency, selectivity, in particular over ACAT1, solubility, and preclinical PK profiles. This compound showed the anticipated excellent pharmacokinetic properties in human volunteers

Forty years of IVF

This monograph, written by the pioneers of IVF and reproductive medicine, celebrates the history, achievements, and medical advancements made over the last 40 years in this rapidly growing field