Characterization of Ubrogepant: A Potent and Selective Antagonist of the Human Calcitonin Gene-Related Peptide Receptor (P4.10-021)

Objective: Characterize the pharmacologic profile of ubrogepant, a small-molecule, oral, calcitonin gene–related peptide (CGRP) receptor antagonist under investigation for the acute treatment of migraine attacks. Background: CGRP is a potent vasodilatory neurotransmitter that plays a key role in the pathophysiology of migraine. Design/Methods: The relative affinity of ubrogepant for the human, rhesus, rat, mouse, rabbit, and dog CGRP receptors was assessed using competitive radioligand binding assays. The antagonist activity of ubrogepant was evaluated using a functional CGRP-induced cAMP accumulation assay in cloned human CGRP receptors and in calcitonin (CTR), adrenomedullin 1 (AM1), adrenomedullin 2 (AM2), amylin 1 (AMY1), and amylin 3 (AMY3) receptors. Specificity was further assessed against 116 targets using conventional radioligand binding and enzyme assays, as well as the hERG ligand-binding assay. In vivo CGRP receptor antagonist activity of ubrogepant was evaluated in a rhesus pharmacodynamic model of capsaicin-induced dermal vasodilation (CIDV). Results: The binding affinity for native (Ki=0.067 nM) and cloned human (Ki=0.070 nM) and rhesus (Ki=0.079 nM) receptors was similar for ubrogepant, with relatively lower affinities for CGRP receptors of other species (ranging from Ki=9.6 to 47 nM). Ubrogepant potently blocked human α-CGRP–stimulated cAMP response (IC50 of 0.08) and exhibited highly selective antagonist activity in relation to the CGRP receptor compared with other members of the human calcitonin receptor family. Ubrogepant produced concentration-dependent inhibition of CIDV in the rhesus forearm. Population pharmacokinetic/pharmacodynamic modeling of CIDV suggested that ubrogepant has a mean EC50 of 3.2 nM, which may be correlated with an EC90 of approximately 29 nM. Conclusions: Ubrogepant is a competitive antagonist with high affinity, potency, and selectivity for the human CGRP receptor. In vivo, ubrogepant produced a potent concentration-dependent attenuation of CIDV in the rhesus forearm. Disclosure: Dr. Moore has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co., Inc. Dr. Moore holds stock and/or stock options in Merck & Co., Inc which sponsored research in which Dr. Moore was involved as an investigator. Dr. Burgey has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co., Inc.. Dr. Fraley has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co., Inc. Dr. Fraley holds stock and/or stock options in Merck & Co., Inc. which sponsored research in which Dr. Fraley was involved as an investigator. Dr. Fraley holds stock and/or stock options in Merck & Co., Inc. Dr. Danziger has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck and Co., Inc. Dr. Regan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co., Inc. Dr. Li has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co, Inc. Dr. White has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co., Inc. Dr. Banerjee has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Allergan. Dr. Salvatore has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co., Inc.