RESUMO
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.
Assuntos
Fármacos Antiobesidade/síntese química , Pirimidinas/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Tiofenos/síntese química , Administração Oral , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Disponibilidade Biológica , Células CHO , Cricetinae , Cricetulus , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Canais de Potássio Éter-A-Go-Go/fisiologia , Genes Reporter , Meia-Vida , Humanos , Camundongos , Camundongos Obesos , Modelos Moleculares , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologiaRESUMO
Genetic manipulation studies in mice at both the MCH receptor 1 (MCHR1) as well as the MCH peptide levels have implicated MCHR1 as a key player in energy homeostasis. The phenotype exhibited by these studies, that is, increased metabolic rate, resistance to high fat diet, and subsequent weight loss, has spurred considerable efforts to develop antagonists of MCHR1. In continuation of efforts directed toward this goal, the present work capitalizes on the putative binding mode of an MCH antagonist, resulting in the identification of several novel chemotypes that are potent and selective MCHR1 antagonists. In addition, the favorable pharmacokinetics of representative examples has allowed for the evaluation of an MCHR1 antagonist in a high fat diet-induced obese rodent model of obesity. The tolerability of the right-hand side of the template for diverse chemotypes accompanied by favorable effects on weight loss enhances the attractiveness of this template in the pursuit toward development of effective anti-obesity agents.
Assuntos
Fármacos Antiobesidade/síntese química , Pirimidinas/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Tiofenos/síntese química , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Sítios de Ligação , Células CHO , Cricetinae , Cricetulus , Camundongos , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Receptores de Somatostatina/química , Relação Estrutura-Atividade , Tiofenos/farmacocinética , Tiofenos/farmacologiaRESUMO
We investigated the effects of glucocorticoid manipulation on orexin-A-induced feeding and prepro-orexin mRNA levels in the lateral hypothalamic area (LHA) of the rat brain. Adrenalectomy (ADX) reduced orexin-A-induced feeding over 4 h by about 60%, compared with shams, an effect that was reversed by corticosterone (CORT) replacement. ADX had no effect on prepro-orexin mRNA levels in the LHA in either the morning or the evening; however, message was up-regulated by CORT in the morning but not the evening. An increased number of emulsion grains per cell in the LHA suggests that this is a specific increase in prepro-orexin mRNA and is not due to an increased number of cells expressing message. Prepro-orexin mRNA levels in the LHA were elevated 4 h after injection of lipopolysaccharide, compared with saline-injected controls. Partial but not complete abolition of orexin-A-induced feeding by ADX suggests that orexin-A-induced feeding may be mediated through glucocorticoid-dependent and glucocorticoid-independent pathways. In the morning increased prepro-orexin mRNA after CORT replacement demonstrates that orexin expression is sensitive to increased concentrations of glucocorticoids. However, the lack of effect of ADX on prepro-orexin mRNA levels suggests that endogenous glucocorticoids are not involved in tonic regulation of basal prepro-orexin expression. Overall our data constitute a body of evidence for an integrated relationship between central orexin expression, stress, glucocorticoid manipulation, and feeding patterns in the rat.
Assuntos
Anti-Inflamatórios/metabolismo , Corticosterona/metabolismo , Ingestão de Alimentos/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neuropeptídeos/genética , Estresse Fisiológico/fisiopatologia , Adrenalectomia , Animais , Anti-Inflamatórios/farmacologia , Ritmo Circadiano/fisiologia , Corticosterona/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/fisiologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Neuropeptídeos/farmacologia , Orexinas , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/fisiologia , RNA Mensageiro/análise , Ratos , Ratos Sprague-DawleyRESUMO
Optimization of a series of constrained melanin-concentrating hormone receptor 1 (MCH R1) antagonists has provided compounds with potent and selective MCH R1 activity. Details of the optimization process are provided and the use of one of the compounds in an animal model of diet-induced obesity is presented.
Assuntos
Pirimidinonas/química , Pirimidinonas/farmacologia , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Peso Corporal/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos AKR , Modelos Moleculares , Estrutura Molecular , Pirimidinonas/síntese química , Receptores do Hormônio Hipofisário/metabolismo , Relação Estrutura-Atividade , Compostos de Sulfidrila/químicaRESUMO
The identification of an MCH R1 antagonist screening hit led to the optimization of a class of benzimidazole-based MCH R1 antagonists. Structure-activity relationships and efforts to optimize pharmacokinetic properties are detailed along with the demonstration of the effectiveness of an MCH R1 antagonist in an animal model of obesity.