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
| Autor: | Stanley Wertheimer, Lee Apostle Mcdermott, Stuart Hayden, Weiya Yun, Yingsi Chen, Anjula Pamidimukkala, Rebecca Taub, Kuo-Sen Huang, Toni Whittard, Liang Guo, Shiming Li, Jenny Tan, Fariborz Firooznia, Adrian Wai-Hing Cheung, David Robert Bolin, Nicholas Marcopulos, Yimin Qian, Karin Conde-Knape, Mushtaq Ahmad, Gwendolyn Ramsey, Cristina M. Rondinone, Jefferson Wright Tilley, Matthew Michael Hamilton |
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| Rok vydání: | 2011 |
| Předmět: |
Male
medicine.medical_specialty medicine.drug_class Carboxylic acid Carboxylic Acids Administration Oral Carboxamide Cell Line Acylation Inhibitory Concentration 50 Mice Dogs Internal medicine Drug Discovery Diabetes Mellitus medicine Animals Humans Diacylglycerol O-Acyltransferase Obesity Enzyme Inhibitors Oxazoles Diacylglycerol kinase chemistry.chemical_classification biology medicine.disease Amides Ether-A-Go-Go Potassium Channels Enzyme assay Rats Enzyme Endocrinology chemistry biology.protein Molecular Medicine Metabolic syndrome Diet-induced obese |
| Zdroj: | Journal of Medicinal Chemistry. 54:2433-2446 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm101580m |
| Popis: | 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, p.o., qd) during a 21-day efficacy study. Furthermore, compound 29 demonstrated improved glucose tolerance determined by an oral glucose tolerance test (OGTT). |
| Databáze: | OpenAIRE |
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