RESUMO
S1P5 is one of the five sphingosine-1-phosphate (S1P) receptors which play important roles in immune and CNS cell homeostasis, growth, and differentiation. Little is known about the effect of modulation of S1P5 due to the lack of S1P5 specific modulators with suitable druglike properties. Here we describe the discovery and optimization of a novel series of potent selective S1P5 antagonists and the identification of an orally active brain-penetrant tool compound 15.
RESUMO
The peptide hormone ghrelin is the endogenous ligand for the type 1a growth hormone secretagogue receptor (GHS-R1a) and the only currently known circulating appetite stimulant. GHS-R1a antagonism has therefore been proposed as a potential approach for obesity treatment. More recently, ghrelin has been recognized to also play a role in controlling glucose-induced insulin secretion, which suggests another possible benefit for a GHS-R1a antagonist, namely, the role as an insulin secretagogue with potential value for diabetes treatment. In our laboratories, piperidine-substituted quinazolinone derivatives were identified as a new class of small-molecule GHS-R1a antagonists. Starting from an agonist with poor oral bioavailability, optimization led to potent, selective, and orally bioavailable antagonists. In vivo efficacy evaluation of selected compounds revealed suppression of food intake and body weight reduction as well as glucose-lowering effects mediated by glucose-dependent insulin secretion.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Obesidade/tratamento farmacológico , Quinazolinonas/síntese química , Receptores de Grelina/antagonistas & inibidores , Administração Oral , Animais , Ligação Competitiva , Glicemia/análise , Linhagem Celular , Ingestão de Alimentos/efeitos dos fármacos , Teste de Tolerância a Glucose , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinazolinonas/química , Quinazolinonas/farmacologia , Ensaio Radioligante , Ratos , Ratos Wistar , Estereoisomerismo , Relação Estrutura-Atividade , Redução de Peso/efeitos dos fármacosRESUMO
Bis-aryl ureas have been disclosed previously as a potent class of Raf kinase inhibitors. Modifications in the amide portion led to an improvement in aqueous solubility, an important characteristic for an oral drug. Based on this finding, we hypothesize that this portion of the molecule is directed towards the solvent in Raf-1.
