Discovery of benzothiazole derivatives as efficacious and enterocyte-specific MTP inhibitors |
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Authors: | Chi B. Vu Jill C. Milne David P. Carney Jeffrey Song Wendy Choy Philip D. Lambert David J. Gagne Michael Hirsch Angela Cote Meghan Davis Elden Lainez Nekeya Meade Karl Normington Michael R. Jirousek Robert B. Perni |
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Affiliation: | Sirtris Pharmaceuticals, Departments of Medicinal Chemistry, Lead Discovery and Pharmacology, 200 Technology Square, Cambridge, MA 02139, USA |
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Abstract: | A series of triamide derivatives bearing a benzothiazole core is shown to be potent microsomal triglyceride transfer protein (MTP) inhibitors. In order to minimize liver toxicity, these compounds have been optimized to have activity only in the enterocytes and have limited systemic bioavailability. Upon oral administration, selected analogs within this series have been further demonstrated to reduce food intake along with body weight and thereby improve glucose homeostasis and insulin sensitivity in a 28-day mice diet-induced obesity (DIO) model. |
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