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

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• 作者：Jonas G. Barlind ; Udo A. Bauer ; Alan M. Birch ; Susan Birtles ; Linda K. Buckett ; Roger J. Butlin ; Robert D. M. Davies ; Jan W. Eriksson ; Clare D. Hammond ; Ragnar Hovland ; Petra Johannesson ; Magnus J. Johansson ; Paul D. Kemmitt ; Bo T. Lindmark ; Pablo Morentin Gutierrez ; Tobias A. Noeske ; Andreas Nordin ; Charles J. O鈥橠onnell ; Annika U. Petersson ; Alma Redzic ; Andrew V. Turnbull ; Johanna Vinblad
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December 13, 2012
• 年：2012
• 卷：55
• 期：23
• 页码：10610-10629
• 全文大小：778K
• 年卷期：v.55,no.23(December 13, 2012)
• ISSN：1520-4804

文摘

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.