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

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 30 (...

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Veröffentlicht in:Journal of medicinal chemistry 2012-12, Vol.55 (23), p.10610-10629
Hauptverfasser: Barlind, Jonas G., Bauer, Udo A., Birch, Alan M., Birtles, Susan, Buckett, Linda K., Butlin, Roger J., Davies, Robert D. M., Eriksson, Jan W., Hammond, Clare D., Hovland, Ragnar, Johannesson, Petra, Johansson, Magnus J., Kemmitt, Paul D., Lindmark, Bo T., Morentin Gutierrez, Pablo, Noeske, Tobias A., Nordin, Andreas, O’Donnell, Charles J., Petersson, Annika U., Redzic, Alma, Turnbull, Andrew V., Vinblad, Johanna
Format: Artikel
Sprache:eng
Schlagworte:
Acetates - chemistry
Acetates - pharmacokinetics
Acetates - pharmacology
Animals
Diacylglycerol O-Acyltransferase - antagonists & inhibitors
Drug Evaluation, Preclinical
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacokinetics
Enzyme Inhibitors - pharmacology
Humans
Magnetic Resonance Spectroscopy
Pyrazines - chemistry
Pyrazines - pharmacokinetics
Pyrazines - pharmacology
Rats
Solubility
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Zusammenfassung: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 30 (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.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/jm301296t