The pivotal role of calcitonin gene-related peptide (CGRP) in migraine 
pathophysiology was identified over 30 years ago, but the successful clinical 
development of targeted therapies has only recently been realized. This 
Perspective traces the decades long evolution of medicinal chemistry required to 
advance small molecule CGRP receptor antagonists, also called gepants, including 
the current clinical agents rimegepant, vazegepant, ubrogepant, and atogepant. 
Providing clinically effective blockade of CGRP signaling required surmounting 
multiple challenging hurdles, including defeating a sizable ligand with 
subnanomolar affinity for its receptor, designing antagonists with an extended 
confirmation and multiple pharmacophores while retaining solubility and oral 
bioavailability, and achieving circulating free plasma levels that provided near 
maximal CGRP receptor coverage. The clinical efficacy of oral and intranasal 
gepants and the injectable CGRP monoclonal antibodies (mAbs) are described, as 
are recent synthetic developments that have benefited from new structural 
biology data. The first oral gepant was recently approved and heralds a new era 
in the treatment of migraine.