Preparation of imidazoles as potent calcitonin gene-related peptide (CGRP) antagonists

Several new potent CGRP receptorantagonists have been prepared in which the amide bond of lead compound1 has been replaced by bioisosteric imidazolemoieties. Substitution at N-1 of the imidazolewas optimized to afford compounds with comparable potency to that of lead 1. Conformational restraint of the imidazoleto form tetrahydroimidazo[1,5-a] pyrazine43 gave substantially improved permeability.