期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 21, 期 20, 页码 6122-6125出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2011.08.028
关键词
DGAT-1; Inhibition; Dioxino[2,3-d]pyrimidine; Obesity; Diabetes; Triglycerides
A novel series of potent DGAT-1 inhibitors was developed originating from the lactam-based clinical candidate PF-04620110. Incorporation of a dioxino[2,3-d]pyrimidine-based core afforded good alignment of pharmacophore features and resulted in improved passive permeability. Development of an efficient, homochiral synthesis of these targets facilitated confirmation of predictions regarding the stereochemical-dependence of DGAT-1 inhibition for this series. Compound 10 was shown to be a potent inhibitor of human DGAT-1 (10 nM) and to suppress triglyceride synthesis at oral doses of <3 mg/kg. (C) 2011 Elsevier Ltd. All rights reserved.
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