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.