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