Chronic migraine, defined as migraine headache occurring on at least 15 days each month, is a highly disabling disorder, yet there are no disease-specific treatments for migraine prevention.  Calcitonin gene-related peptide (CGRP) has been shown to play in important role in migraine headache and small molecule CGRP receptor antagonists, including telcagepant, have demonstrated clinical efficacy for the acute treatment of migraine.  More recently, several monoclonal antibodies that target either CGRP or the CGRP receptor were shown to be effective for migraine prevention. A study evaluating BID dosing of telcagepant (140 and 280 mg) for 12 weeks suggested that this small molecule antagonist was also efficacious for migraine prevention, although the trial was terminated early due to hepatotoxicity concerns.  In order to identify a development candidate with reduced risk of liver injury, we focused on compounds with differentiated structure and metabolism from earlier compounds associated with hepatotoxicity.  Our strategy also involved structure modifications designed to reduce bioactivation, increase potency, and lower the projected dose.  These considerations led to the discovery of AGN-241689 (MK-8031), which combines good oral pharmacokinetic properties with exquisite potency and selectivity. The presentation will discuss the discovery and preclinical profile of AGN-241689 in detail.  The compound is currently being studied in the clinic as a novel therapeutic for migraine prophylaxis. <br/>

Discovery of AGN-241689: A potent, orally-acting CGRP receptor antagonist for migraine prophylaxis

253rd National Meeting (2017)

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