| Autor: |
X. Tavares, Francis, A. Al-Barazanji, Kamal, C. Bigham, Eric, J. Bishop, Michael, S. Britt, Christy, L. Carlton, David, L. Feldman, Paul, S. Goetz, Aaron, K. Grizzle, Mary, C. Guo, Yu, L. Handlon, Anthony, L. Hertzog, Donald, M. Ignar, Diane, G. Lang, Daniel, J. Ott, Ronda, J. Peat, Andrew, Zhou, Hui-Qiang |
| Zdroj: |
Journal of Medicinal Chemistry; November 2006, Vol. 49 Issue: 24 p7095-7107, 13p |
| Abstrakt: |
The high expression of MCH in the hypothalamus with the lean hypophagic phenotype coupled with increased resting metabolic rate and resistance to high fat diet-induced obesity of MCH KO mice has spurred considerable efforts to develop small molecule MCHR1 antagonists. Starting from a lead thienopyrimidinone series, structure-activity studies at the 3- and 6-positions of the thienopyrimidinone core afforded potent and selective MCHR1 antagonists with representative examples having suitable pharmacokinetic properties. Based on structure-activity relationships, a structural model for MCHR1 was constructed to explain the binding mode of these antagonists. In general, a good correlation was observed between pKas and activity in the right-hand side of the template, with Asp123 playing an important role in the enhancement of binding affinity. A representative example when evaluated chronically in diet-induced obese mice resulted in good weight loss effects. These antagonists provide a viable lead series in the discovery of new therapies for the treatment of obesity. |
| Databáze: |
Supplemental Index |
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