mk-3207 and Migraine-Disorders

Calcitonin gene-related peptide (CGRP) is a potent neuromodulator and vasodilator. It has been implicated in the pathogenesis of migraine by a number of lines of evidence, although its precise role has yet to be fully defined. Compelling evidence for the importance of CGRP in migraine has been provided by clinical trials with multiple small molecule CGRP receptor antagonists. These clinical studies have shown that blockade of the CGRP receptor can produce antimigraine efficacy comparable to that of the gold standard triptan class of drugs with an incidence of adverse events that appears to be relatively low. The present review describes the discovery and development of these new antimigraine agents and highlights the challenges of identifying orally acting drugs that target a family B G-protein-coupled receptor.

Topics: Amino Acid Sequence; Animals; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials as Topic; Drug Discovery; Humans; Migraine Disorders; Molecular Sequence Data; Receptors, Calcitonin Gene-Related Peptide; Structure-Activity Relationship

Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown to be efficacious as abortive migraine therapeutics with the absence of cardiovascular liabilities that are associated with triptans. Herein, we report the discovery of a highly potent CGRP receptor antagonist, BMS-742413, with the potential to provide rapid onset of action through intranasal delivery. The compound displays excellent aqueous solubility, oxidative stability, and toxicological profile. BMS-742413 has good intranasal bioavailability in the rabbit and shows a robust, dose-dependent inhibition of CGRP-induced increases in marmoset facial blood flow.

Topics: Administration, Intranasal; Amides; Animals; Caco-2 Cells; Calcitonin Gene-Related Peptide Receptor Antagonists; Callithrix; Coronary Vessels; Drug Evaluation, Preclinical; Face; Humans; Indazoles; Migraine Disorders; Quinolones; Rabbits; Rats; Receptors, Calcitonin Gene-Related Peptide; Respiratory Mucosa

Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo.

Topics: Administration, Oral; Analgesics; Animals; Biological Availability; Calcitonin Gene-Related Peptide Receptor Antagonists; Disease Models, Animal; Dogs; Humans; Macaca mulatta; Mice; Migraine Disorders; Pyridines; Rats; Receptors, Calcitonin Gene-Related Peptide; Species Specificity; Spiro Compounds