Calcitonin gene-related peptide (CGRP) is a potent neuropeptide that plays a key 
role in the pathophysiology of migraine headache. CGRP levels in the cranial 
circulation are increased during a migraine attack, and CGRP itself has been 
shown to trigger migraine-like headache. The correlation between CGRP release 
and migraine headache points to the potential utility of CGRP receptor 
antagonists as novel therapeutics in the treatment of migraine. Indeed, clinical 
proof-of-concept in the acute treatment of migraine was demonstrated with an 
intravenous formulation of the CGRP receptor antagonist BIBN4096BS (olcegepant). 
Here we report on the pharmacological characterization of the first orally 
bioavailable CGRP receptor antagonist in clinical development, MK-0974 
[N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide]. 
In vitro, MK-0974 is a potent antagonist of the human (K(i) = 0.77 nM) and 
rhesus (K(i) = 1.2 nM) CGRP receptors but displays >1500-fold lower affinity for 
the canine and rat receptors as determined via (125)I-human CGRP competition 
binding assays. A rhesus pharmacodynamic assay measuring capsaicin-induced 
changes in forearm dermal blood flow via laser Doppler imaging was utilized to 
determine the in vivo activity of CGRP receptor antagonism. MK-0974 produced a 
concentration-dependent inhibition of dermal vasodilation, generated by 
capsaicin-induced release of endogenous CGRP, with plasma concentrations of 127 
and 994 nM required to block 50 and 90% of the blood flow increase, 
respectively. In conclusion, MK-0974 is a highly potent, selective, and orally 
bioavailable CGRP receptor antagonist, which may be valuable in the acute 
treatment of migraine.