1 Calcitonin Gene-Related Peptide Receptor Antagonists for the Treatment of Migraine

Abstract

This chapter presents the characterization of calcitonin gene-related peptide (CGRP) receptor antagonists for the therapeutic application in the treatment of migraine. CGRP had been identified as a vasoactive neuropeptide that is largely expressed in sensory neurons. The plasma levels of CGRP are elevated during migraine and successful treatment with a triptan return it to basal levels. This observation, along with other evidence, suggests that CGRP receptor antagonists might be useful in antimigraine drugs. CGRP is widely distributed in the peripheral and central nervous system and exhibits a wide range of biological effects on tissues, the most pronounced being vasodilation. The discovery of small molecule CGRP receptor antagonists has generally begun with weak, micromolar high-throughput screening (HTS) lead being optimized to potent antagonists such as BIBN4096BS and MK-0974. Lead optimization of the weakly active benzodiazepinone spirohydantoin focused on improving the functional CGRP receptor antagonism, first in cell culture with added human serum and then in vivo in a noninvasive rhesus monkey pharmacodynamic (PD) model using topical capsaicin-induced dermal vasodilation(CIDV).