Potent, selective, and orally efficacious antagonists of melanin-concentrating hormone receptor 1.
J Med Chem
; 49(24): 7095-107, 2006 Nov 30.
Article
em En
| MEDLINE
| ID: mdl-17125262
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Tiofenos
/
Receptores de Somatostatina
/
Fármacos Antiobesidade
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Estados Unidos