RESUMO
Insomnia affects a growing portion of the adult population in the U.S. Most current therapeutic approaches to insomnia primarily address sleep onset latency. Through the 5-hydroxytryptamine(2A) (5-HT(2A)) receptor, serotonin (5-HT) plays a role in the regulation of sleep architecture, and antagonists/inverse-agonists of 5-HT(2A) have been shown to enhance slow wave sleep (SWS). We describe here a series of 5-HT(2A) inverse-agonists that when dosed in rats, both consolidate the stages of NREM sleep, resulting in fewer awakenings, and increase a physiological measure of sleep intensity. These studies resulted in the discovery of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl]-3-(2,4-difluorophenyl)urea (Nelotanserin), a potent inverse-agonist of 5-HT(2A) that was advanced into clinical trials for the treatment of insomnia.
Assuntos
Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Ligação Competitiva , Concentração Inibidora 50 , Masculino , Compostos de Fenilureia/farmacocinética , Pirazóis/farmacocinética , Ratos , Ratos Wistar , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Serotonina/metabolismo , Sono/efeitos dos fármacos , Distúrbios do Início e da Manutenção do Sono/metabolismo , Relação Estrutura-AtividadeRESUMO
The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
Assuntos
Fármacos Antiobesidade/síntese química , Benzazepinas/síntese química , Obesidade/tratamento farmacológico , Agonistas do Receptor 5-HT2 de Serotonina , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Benzazepinas/farmacocinética , Benzazepinas/farmacologia , Linhagem Celular , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Aumento de Peso/efeitos dos fármacosRESUMO
A series of 4-(dimethylamino)quinazoline based antagonists of the melanin-concentrating hormone receptor 1 (MCH-R1) is described. This series was derived from a lead compound, AR129330, identified by HTS of a GPCR-directed library using a functional assay with a constitutively activated (CART) form of the receptor. The preliminary optimization resulted in the identification of compounds 20, 21, and 23.
Assuntos
Quinazolinas/química , Quinazolinas/farmacologia , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Linhagem Celular , Humanos , Relação Estrutura-AtividadeRESUMO
We report on the synthesis, biological evaluation and structure-activity relationships for a series of 3-benzazepine derivatives as 5-HT(2C) receptor agonists. The compounds were evaluated in functional assays measuring [3H] phosphoinositol turnover in HEK-293 cells transiently transfected with h5-HT(2C), h5-HT(2A) or h5-HT(2B) receptors. Several compounds are shown to be potent and selective 5-HT(2C) receptor agonists, which decrease food intake in a rat feeding model.
