RESUMEN
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.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Diseño de Fármacos , Trastornos Migrañosos/tratamiento farmacológico , Oxadiazoles/síntesis química , Oxadiazoles/uso terapéutico , Administración Oral , Animales , Modelos Moleculares , Estructura Molecular , Oxadiazoles/química , RatasRESUMEN
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.
Asunto(s)
Química Farmacéutica/métodos , Ghrelina/química , Receptores de Ghrelina/antagonistas & inhibidores , Sulfonas/química , Administración Oral , Animales , Disponibilidad Biológica , Diseño de Fármacos , Hormona del Crecimiento/química , Masculino , Modelos Químicos , Procesamiento Proteico-Postraduccional , Ratas , Ratas Sprague-Dawley , Receptores de Ghrelina/química , Relación Estructura-ActividadRESUMEN
A series of small molecule orally bioavailable ghrelin receptor agonists have been identified through systematic optimisation of a high throughput screening hit.