Calcitonin gene-related peptide (CGRP) plays an important role in migraine headache and inhibition of the function of CGRP has been demonstrated to be an effective approach to migraine treatment with both small molecule and monoclonal antibody modalities. We previously described the identification of novel aminopyridine-based CGRP receptor antagonists as part of a program to identify orally active CGRP receptor antagonists. While these compounds exhibited good potency and oral bioavailability, they possessed only modest selectivity for the CGRP receptor over the closely related amylin (AMY1) receptor. We now describe a structure-based approach to improving the CGRP to AMY1 receptor selectivity of this class of aminopyridines. While the binding site of these compounds is largely conserved between the CGRP and AMY1 receptors, analysis of the X-ray crystal structure of a lead aminopyridine revealed key interactions that could potentially be exploited to confer enhanced selectivity. Inspired by this analysis, rational modification of the lead structure led to compounds with improved affinity for the CGRP receptor and &gt; 100-fold selectivity versus the AMY1 receptor. Gratifyingly, BioNMR studies confirmed that the selective compounds interacted with targeted residues in the CGRP receptor as planned. This strategy led to the identification of novel CGRP receptor antagonists with subnanomolar potency and excellent selectivity vs. the AMY1 receptor.

Structure-based design of potent and selective CGRP receptor antagonists for the treatment of migraine

2019 Fall National Meeting

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