A growing body of evidence has implicated the
calcitonin gene-related peptide (
CGRP) receptors in
migraine pathophysiology. With the recent approval of
monoclonal antibodies targeting CGRP or the
CGRP receptor, the inhibition of CGRP-mediated signaling has emerged as a promising approach for preventive treatments of
migraine in adults. However, there are no small-molecule anti-CGRP treatments available 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 α-CGRP 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 CSF/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
calcitonin generelated
peptide receptor. In vivo studies using a pharmacodynamic model of
capsaicin-induced dermal vasodilation (CIDV) in rhesus monkeys and humans demonstrated that
ubrogepant produced concentration-dependent inhibition of CIDV, indicating a predictable pharmacokinetic-pharmacodynamic relationship.