Small-molecule
calcitonin gene-related peptide (
CGRP) receptor antagonists have demonstrated therapeutic efficacy for the treatment of
migraine. However, previously investigated
CGRP receptor antagonists,
telcagepant and
MK-3207, were discontinued during clinical development because of concerns about
drug-induced liver injury. A subsequent effort to identify novel
CGRP receptor antagonists less likely to cause hepatotoxicity led to the development of
ubrogepant. The selection of
ubrogepant, following a series of mechanistic studies conducted with
MK-3207 and
telcagepant, was focused on key structural modifications suggesting that
ubrogepant was less prone to forming reactive metabolites than previous compounds. The potential for each
drug to cause liver toxicity was subsequently assessed using a quantitative systems toxicology approach (DILIsym) that incorporates quantitative assessments of
mitochondrial dysfunction, disruption of
bile acid homeostasis, and oxidative stress, along with estimates of dose-dependent
drug exposure to and within liver cells. DILIsym successfully modeled liver toxicity for
telcagepant and
MK-3207 at the dosing regimens used in clinical trials. In contrast, DILIsym predicted no hepatotoxicity during treatment with
ubrogepant, even at daily doses up to 1000 mg (10-fold higher than the approved clinical dose of 100 mg). These predictions are consistent with clinical trial experience showing that
ubrogepant has lower potential to cause hepatotoxicity than has been observed with
telcagepant and
MK-3207.