| Discovery of Orally Active Carboxylic Acid Derivatives of 2-Phenyl-5-trifluoromethyloxazole-4-carboxamide as Potent Diacylglycerol Acyltransferase-1 Inhibitors for the Potential Treatment of Obesity and Diabetes. | |
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MedLine Citation:
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PMID: 21413799 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Diacylglycerol acyltransferase-1 (DGAT-1) is the enzyme that catalyzes the final and committed step of triglyceride formation, namely, the acylation of diacylglycerol with acyl coenzyme A. DGAT-1 deficient mice demonstrate resistance to weight gain on high fat diet, improved insulin sensitivity, and reduced liver triglyceride content. Inhibition of DGAT-1 thus represents a potential novel approach for the treatment of obesity, dyslipidemia, and metabolic syndrome. In this communication, we report the identification of the lead structure 6 and our lead optimization efforts culminating in the discovery of potent, selective, and orally efficacious carboxylic acid derivatives of 2-phenyl-5-trifluoromethyloxazole-4-carboxamides. In particular, compound 29 (DGAT-1 enzyme assay, IC(50) = 57 nM; CHO-K1 cell triglyceride formation assay, EC(50) = 0.5 μM) demonstrated dose dependent inhibition of weight gain in diet induced obese (DIO) rats (0.3, 1, and 3 mg/kg, PO, qd) during a 21-day efficacy study. Furthermore, compound 29 demonstrated improved glucose tolerance determined by an oral glucose tolerance test (OGTT). |
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Authors:
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Yimin Qian; Stanley J Wertheimer; Mushtaq Ahmad; Adrian Wai-Hing Cheung; Fariborz Firooznia; Matthew M Hamilton; Stuart Hayden; Shiming Li; Nicholas Marcopulos; Lee McDermott; Jenny Tan; Weiya Yun; Liang Guo; Anjula Pamidimukkala; Yingsi Chen; Kuo-Sen Huang; Gwendolyn B Ramsey; Toni Whittard; Karin Conde-Knape; Rebecca Taub; Cristina M Rondinone; Jefferson Tilley; David Bolin |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-3-17 |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: - ISSN: 1520-4804 ISO Abbreviation: - Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-3-18 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Discovery Chemistry, ‡Non-Clinical Drug Safety, §Metabolism and Pharmacokinetics, ∥Discovery Technologies, and ⊥Metabolic and Vascular Diseases, Hoffmann-La Roche Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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