Abstract
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.
Highlights
Migraine is a highly prevalent, chronic neurologic disease and the leading cause of disability in people aged 15–49 years (Burch et al, 2018; Steiner et al, 2018)
Ubrogepant is an orally bioavailable calcitonin gene–related peptide (CGRP) receptor antagonist developed for the acute treatment of migraine
Ubrogepant is a potent CGRP receptor antagonist developed for use in the acute treatment of migraine
Summary
Migraine is a highly prevalent, chronic neurologic disease and the leading cause of disability in people aged 15–49 years (Burch et al, 2018; Steiner et al, 2018). This work was previously presented in abstract form: Moore E, Burgey CS, Fraley M, Danziger A, Regan C, Li CC, White RB, Banerjee P, Salvatore C (2019). Characterization of ubrogepant: a potent and selective antagonist of the human calcitonin gene-related peptide receptor. Disclosures: E.M., M.E.F., I.M.B., C.S.B., R.B.W., C.-C.L., C.P.R., A.D., M.S.M., E.H., and C.S. are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.,, (Kenilworth, NJ,) and own/hold stock/stock options of Merck & Co., Inc., (Kenilworth, NJ.) P.B. is an employee of Allergan plc (Madison, NJ) and owns stock in the company.
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