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

Moore, Eric L.; Fraley, Mark E.; Bell, Ian M.; Burgey, Christopher S.; White, Rebecca B.; Li, Chi-Chung; Regan, Christopher P.; Danziger, Andrew; Michener, Maria S.; Hostetler, Eric D.; Banerjee, Pradeep; Salvatore, Christopher

doi:10.1124/jpet.119.261065

Cited by 48 publications

(66 citation statements)

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“…These data suggest that the antagonist potency of gepants at the AMY 1 receptor may be underestimated in several studies. For instance, the potency of ubrogepant and atogepant may be higher at the AMY 1 receptor than currently reported where only data for amylin is currently available (Hargreaves and Olesen, 2019;Moore et al, 2020).…”

Section: Discussionmentioning

confidence: 84%

Antagonism of CGRP Signaling by Rimegepant at Two Receptors

et al. 2020

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The "gepants" are a class of calcitonin gene-related peptide (CGRP) receptor antagonist molecules that have been developed for the prevention and treatment of migraine. Rimegepant is reported to act at the CGRP receptor, has good oral bioavailability, and has had positive clinical trial results. However, there is very little data available describing its receptor pharmacology. Importantly, rimegepant activity at the AMY 1 receptor, a second potent CGRP receptor that is known to be expressed in the trigeminovascular system, has not been reported. The ability of rimegepant to antagonize activation of human CGRP, AMY 1 , and related adrenomedullin receptors was determined in transfected in Cos7 cells. Rimegepant was an effective antagonist at both the CGRP and AMY 1 receptor. The antagonism of both CGRP and AMY 1 receptors may have implications for our understanding of the mechanism of action of rimegepant in the treatment of migraine.

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Section: Discussionmentioning

confidence: 84%

Antagonism of CGRP Signaling by Rimegepant at Two Receptors

et al. 2020

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“…Ubrogepant demonstrated potent inhibition of the human α-CGRPstimulated cyclic AMP response in human CGRP receptorexpressing HEK293 cells (50% inhibitory concentration of 0.08 nmol/L). Relative to other receptors in the calcitonin receptor family, ubrogepant exhibited highly selective antagonist activity against CGRP receptors [7].…”

Section: Pharmacodynamicsmentioning

confidence: 99%

Ubrogepant: First Approval

Scott

2020

Drugs

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Ubrogepant (Ubrelvy™) is an orally administered, small molecule, highly-selective, calcitonin gene-related peptide (CGRP) antagonist that was developed by Allergan under license to Merck & Co. as an acute treatment for migraine. In December 2019, ubrogepant received its first global approval in the USA for the acute treatment of migraine (± aura) in adults. This article summarizes the milestones in the development of ubrogepant leading to its first global approval for the acute treatment of migraine (± aura) in adults. Ubrogepant (Ubrelvy™): Key points A calcitonin gene-related peptide receptor antagonist was being developed by Allergan under license to Merck & Co. for the acute treatment of migraine

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“…Centrally, these receptors can be found on terminals of trigeminal afferents, in the brain stem, cerebellum, and cerebral hemispheres ( 45 ). Although CGRP receptors at all these sites may be relevant to migraine, ubrogepant poorly penetrates the blood-brain barrier, suggesting that the major site of action is likely on the periphery ( 46 ). This conclusion is consistent with studies that have demonstrated that peripheral CGRP can trigger migraine pain ( 47 ) and that monoclonal antibodies that do not significantly penetrate the blood-brain barrier can effectively reduce the frequency of migraine attacks ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

Ubrogepant does not induce latent sensitization in a preclinical model of medication overuse headache

et al. 2020

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Background Ubrogepant, a small-molecule calcitonin gene-related peptide receptor antagonist, was recently approved as an oral medication for the acute treatment of migraine. This study aimed to determine whether ubrogepant shows efficacy in a preclinical model of migraine-like pain and whether repeated oral administration of ubrogepant induces latent sensitization relevant to medication overuse headache in rats. Methods A “two-hit” priming model of medication overuse headache was used. Female Sprague-Dawley rats received six oral doses of sumatriptan 10 mg/kg over 2 weeks to induce latent sensitization (i.e. “priming”). Cutaneous allodynia was measured periodically over 20 days in the periorbital and hindpaw regions using von Frey filaments. The rats were then subjected to a 1-hour bright light stress challenge on two consecutive days. At the start of the second bright light stress exposure, oral sumatriptan 10 mg/kg, oral ubrogepant 25, 50, or 100 mg/kg, or vehicle was administered; thereafter, cephalic and hindpaw sensory thresholds were monitored hourly over 5 hours to determine the efficacy of ubrogepant in reversing bright light stress-induced cutaneous allodynia. A dose of ubrogepant effective in the medication overuse headache model (100 mg/kg) was then selected to determine if repeated administration would produce latent sensitization. Rats were administered six oral doses of ubrogepant 100 mg/kg, sumatriptan 10 mg/kg (positive control), or vehicle over 2 weeks, and cutaneous allodynia was evaluated regularly. Testing continued until mechanosensitivity returned to baseline levels. Rats were then challenged with bright light stress on days 20 and 21, and periorbital and hindpaw cutaneous allodynia was measured. On days 28 to 32, the same groups received a nitric oxide donor (sodium nitroprusside 3 mg/kg, i.p.), and cutaneous allodynia was assessed hourly over 5 hours. Results Sumatriptan elicited cutaneous allodynia in both cephalic and hindpaw regions; cutaneous allodynia resolved to baseline levels after cessation of drug administration (14 days). Sumatriptan priming resulted in generalized and delayed cutaneous allodynia, evoked by either bright light stress (day 21) or nitric oxide donor (day 28). Ubrogepant dose-dependently blocked both stress- and nitric oxide donor-induced cephalic and hindpaw allodynia in the sumatriptan-induced medication overuse headache model with a 50% effective dose of ∼50 mg/kg. Unlike sumatriptan, ubrogepant 100 mg/kg in repeated effective doses did not produce cutaneous allodynia or latent sensitization. Conclusions Both ubrogepant and sumatriptan demonstrated efficacy as acute medications for stress- and nitric oxide donor-evoked cephalic allodynia in a preclinical model of medication overuse headache, consistent with their clinical efficacy in the acute treatment of migraine. However, in contrast to sumatriptan, repeated treatment with ubrogepant did not induce cutaneous allodynia or latent sensitization. These studies suggest ubrogepant may offer an effective acute treatment of migraine without risk of medication overuse headache. Trial Registration Number: Not applicable

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

Cited by 48 publications

References 50 publications

Antagonism of CGRP Signaling by Rimegepant at Two Receptors

Antagonism of CGRP Signaling by Rimegepant at Two Receptors

Ubrogepant: First Approval

Ubrogepant does not induce latent sensitization in a preclinical model of medication overuse headache

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