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.