RESUMO
A pharmacophore model was built, based on known CGRP receptor antagonists, and this was used to aid the identification of novel leads. Analogues were designed, modelled and synthesised which incorporated alternative 'LHS' fragments linked via either an amide or urea to a privileged 'RHS' fragment commonly found in CGRP receptor antagonists. As a result a novel series of oxadiazole CGRP receptor antagonists has been identified and the subsequent optimisation to enhance both potency and bioavailability is presented.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Desenho de Fármacos , Transtornos de Enxaqueca/tratamento farmacológico , Oxidiazóis/síntese química , Oxidiazóis/uso terapêutico , Administração Oral , Animais , Modelos Moleculares , Estrutura Molecular , Oxidiazóis/química , RatosRESUMO
As part of an on-going lead optimisation effort, a cross screening exercise identified an aryl sulphonyl amide hit that was optimised to afford a highly potent series of ghrelin receptor agonists.
Assuntos
Química Farmacêutica/métodos , Grelina/química , Receptores de Grelina/antagonistas & inibidores , Sulfonas/química , Administração Oral , Animais , Disponibilidade Biológica , Desenho de Fármacos , Hormônio do Crescimento/química , Masculino , Modelos Químicos , Processamento de Proteína Pós-Traducional , Ratos , Ratos Sprague-Dawley , Receptores de Grelina/química , Relação Estrutura-AtividadeRESUMO
A series of small molecule orally bioavailable ghrelin receptor agonists have been identified through systematic optimisation of a high throughput screening hit.