Fragment-Based Discovery of an Oral Calcitonin Gene-Related Peptide Receptor Antagonist for the Treatment of Migraine

Calcitonin gene-related peptide (CGRP) receptor antagonists
have
demonstrated clinical efficacy in the treatment of migraine. In this
study, we performed surface plasmon resonance-based fragment screening
to identify various site binders and estimated their binding modes
based on surface plasmon resonance and nuclear magnetic resonance
studies using mutated CGRP receptors. Two fragment hits were merged
and optimized to create compound 15, which showed good
oral bioavailability in rats, attractive preclinical properties overall,
and robust activity in a primate model of CGRP-induced facial blood
flow.