Characterization of Ubrogepant: A Potent and Selective Antagonist of the Human Calcitonin Gene-Related Peptide Receptor

A growing body of evidence has implicated the calcitonin gene-related peptide (CGRP) receptors in migraine pathophysiology. With the approval of monoclonal antibodies targeting CGRP or the CGRP receptor, the inhibition of CGRP-mediated signaling emerged as a promising approach for preventive treatments of migraine in adults. Recently, small-molecule anti-GRP treatments have shown efficacy for treating migraine. The current studies aimed to characterize the pharmacologic properties of ubrogepant, an orally bioavailable CGRP receptor antagonist for the acute treatment of migraine. In a series of ligand-binding assays, ubrogepant exhibited a high binding affinity for native (K-i = 0.067 nM) and cloned human (K-i = 0.070 nM) and rhesus CGRP receptors (K-i = 0.079 nM), with relatively lower affinities for CGRP receptors from rat, mouse, rabbit, and dog. In functional assays, ubrogepant potently blocked human alpha-CGRP2-stimulated cAMP response (IC50 of 0.08 nM) and exhibited highly selective antagonist activity for the CGRP receptor compared with other members of the human calcitonin receptor family. Furthermore, the in vivo CGRP receptor antagonist activity of ubrogepant was evaluated in a pharmacodynamic model of capsaicin-induced dermal vasodilation (CIDV) in rhesus monkeys and humans. Results demonstrated that ubrogepant produced concentration-dependent inhibition of CIDV with a mean EC50 of 3.2 and 2.6 nM in rhesus monkeys and humans, respectively. Brain penetration studies with ubrogepant in monkeys showed a cerebrospinal fluid:plasma ratio of 0.03 and low CGRP receptor occupancy. In summary, ubrogepant is a competitive antagonist with high affinity, potency, and selectivity for the human CGRP receptor. SIGNIFICANCE STATEMENT Ubrogepant is a potent, selective, orally delivered, small-molecule competitive antagonist of the human CGRP. In vivo studies using a pharmacodynamic model of CIDV in rhesus monkeys and humans demonstrated that ubrogepant produced concentration-dependent inhibition of CIDV, indicating a predictable pharmacokinetic-pharmacodynamic relationship.