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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 26, 2007; DOI: 10.1124/jpet.107.130344

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Received for publication August 17, 2007.
Revised November 20, 2007.
Accepted for publication November 21, 2007.

Pharmacological Characterization of MK-0974, a Potent and Orally Active CGRP Receptor Antagonist for the Treatment of Migraine

Christopher Salvatore 1*, James Hershey 1, Halea Corcoran 1, John Fay 1, Victor Johnston 1, Eric Moore 1, Scott Mosser 1, Christopher Burgey 1, Daniel Paone 1, Anthony Shaw 1, Samuel Graham 1, Joseph Vacca 1, Theresa Williams 1, Kenneth Koblan 1, Stefanie Kane 1

1 Merck Research Laboratories

* Address correspondence to: E-mail: christopher_salvatore{at}merck.com

Abstract

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. Here we report on the pharmacological characterization of the first orally bioavailable CGRP receptor antagonist in clinical development, MK-0974. In vitro, MK-0974 is a potent antagonist of the human (Ki = 0.77 nM) and rhesus (Ki = 1.2 nM) CGRP receptors, but displays > 1500-fold lower affinity for the canine and rat receptors as determined via [125I]-hCGRP 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 vasodilatation, generated by capsaicin-induced release of endogenous CGRP, with plasma concentrations of 127 nM 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.


Key words: Antagonist, CGRP, CL Receptor, Headache, Migraine, RAMP1


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B. J. Van der Schueren, A. Rogiers, F. H. Vanmolkot, A. Van Hecken, M. Depre, S. A. Kane, I. De Lepeleire, S. R. Sinclair, and J. N. de Hoon
Calcitonin Gene-Related Peptide8-37 Antagonizes Capsaicin-Induced Vasodilation in the Skin: Evaluation of a Human in Vivo Pharmacodynamic Model
J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 248 - 255.
[Abstract] [Full Text] [PDF]


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