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. 2024 Jan;44(1):3331024231226186.
doi: 10.1177/03331024231226186.

Pharmacologic characterization of atogepant: A potent and selective calcitonin gene-related peptide receptor antagonist

Eric Moore  1 , Ian M Bell  1 , Mark E Fraley  1 , Christopher S Burgey  1 , Rebecca B White  1 , Chi-Chung Li  1 , Christopher P Regan  1 , Andrew Danziger  1 , Steve P McGaraughty  2 , Ghazal Naseri Kouzehgarani  2 , Christopher Salvatore  1 , Pradeep Banerjee  3
Affiliations
Free article

Pharmacologic characterization of atogepant: A potent and selective calcitonin gene-related peptide receptor antagonist

Eric Moore et al. Cephalalgia. 2024 Jan.
Free article

Abstract

Background: The trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) is identified as an essential element in migraine pathogenesis.

Methods: In vitro and in vivo studies evaluated pharmacologic properties of the CGRP receptor antagonist atogepant. Radioligand binding using 125I-CGRP and cyclic adenosine monophosphate (cAMP) accumulation assays were conducted in human embryonic kidney 293 cells to assess affinity, functional potency and selectivity. Atogepant in vivo potency was assessed in the rat nitroglycerine model of facial allodynia and primate capsaicin-induced dermal vasodilation (CIDV) pharmacodynamic model. Cerebrospinal fluid/brain penetration and behavioral effects of chronic dosing and upon withdrawal were evaluated in rats.

Results: Atogepant exhibited high human CGRP receptor-binding affinity and potently inhibited human α-CGRP-stimulated cAMP responses. Atogepant exhibited significant affinity for the amylin1 receptor but lacked appreciable affinities for adrenomedullin, calcitonin and other known neurotransmitter receptor targets. Atogepant dose-dependently inhibited facial allodynia in the rat nitroglycerine model and produced significant CIDV inhibition in primates. Brain penetration and behavioral/physical signs during chronic dosing and abrupt withdrawal were minimal in rats.

Conclusions: Atogepant is a competitive antagonist with high affinity, potency and selectivity for the human CGRP receptor. Atogepant demonstrated a potent, concentration-dependent exposure/efficacy relationship between atogepant plasma concentrations and inhibition of CGRP-dependent effects.

Keywords: Atogepant; calcitonin gene–related peptide receptor antagonist; migraine; pharmacology.

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Conflict of interest statement

Declaration of conflicting interestsIan M. Bell, Mark E. Fraley, Christopher S. Burgey, Rebecca B. White, Christopher P. Regan and Andrew Danziger are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and own stock in Merck & Co., Inc., Rahway, NJ, USA. Eric Moore, Chi-Chung Li and Christopher Salvatore were employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and own stock in Merck & Co., Inc., Rahway, NJ, USA. Chi-Chung Li is currently an employee of Genentech and may own stock. Steve P. McGaraughty, Ghazal Naseri Kouzehgarani and Pradeep Banerjee are employees of AbbVie and may hold AbbVie stock.

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