Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide widely expressed in the peripheral and central nervous system that has been implicated in the pathogenesis of migraine headache.  Antagonism of the CGRP receptor has been clinically validated to provide effective acute migraine relief comparable to the triptans with an improved adverse event profile.  In our efforts to develop low-dose successors to telcagepant, our first-generation oral clinical candidate, we investigated a series of novel oxazolidinone-based CGRP receptor antagonists.  The development of potent and selective compounds with low potential human doses will be described. Favorable pharmacokinetic and off-target profiles, including excellent ion channel selectivity, were achieved by a design strategy that took physiochemical properties into careful consideration.  Conformational restriction as a means to improve potency and strategies to address potential genotoxicity concerns will also be discussed.

Novel oxazolidinone CGRP receptor antagonists for the acute treatment of migraine

248th National Meeting (2014)

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