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
An operationally straightforward and efficient method for the alkylation of carbamate-protected guanidines with various alkyl halides and mesylates is described. This protocol proceeds via deprotonation of the acidic N-carbamate hydrogen of the guanidine under biphasic conditions using a catalytic amount of a tetrabutylammonium salt as a phase-transfer catalyst. In this manner, highly functionalized guanidines can be obtained. The reaction is tolerant of a wide range of functional groups on both the alkyl halide and guanidine component. In addition, the reaction is sufficiently mild such that simple aqueous workup and filtration through a short silica gel column yields the substituted guanidines in high purity. In conjunction with the EDCI-mediated guanylation of disubstituted thioureas with amines, phase-transfer catalyzed alkylation of guanidines via a one-pot, three-component synthesis of substituted guanidines was achieved.