Rimegepant

Rimegepant (BMS-927711, CAS: 1289023-67-1) is an orally bioavailable, potent antagonist of the calcitonin gene-related peptide (CGRP) receptor developed for the treatment of migraine.

CGRP is a 37-amino-acid neuropeptide that is widely distributed in the central nervous system and contributes to migraine pathophysiology through its potent vasodilatory activity. Plasma CGRP levels increase during migraine attacks, supporting the CGRP signaling pathway as a therapeutic target. The functional CGRP receptor is a G-protein-coupled receptor complex composed of calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and receptor component protein (RCP).

Rimegepant competitively and completely antagonizes the human CGRP receptor, with an IC₅₀ of 0.14 ± 0.01 nM in SK-N-MC cell membrane binding assays using endogenous human CGRP receptors. It also inhibits CGRP-stimulated cAMP production in SK-N-MC cells, confirming functional receptor antagonism, and exhibits favorable membrane permeability in parallel artificial membrane permeability assays. By blocking CGRP receptor signaling, rimegepant suppresses CGRP-mediated responses involved in migraine and provides an orally available alternative to parenteral CGRP-targeted therapies.

In a large phase 2b clinical trial, oral rimegepant at 10-600 mg was evaluated for the acute treatment of migraine, with placebo and 100 mg sumatriptan as comparators. Rimegepant produced significant improvements in the proportion of patients achieving headache freedom 2 hours after treatment at 75, 150, and 300 mg compared with placebo, whereas increasing the dose to 600 mg did not provide additional efficacy.

Rimegepant was one of the first orally bioavailable CGRP antagonists approved for migraine therapy. It received FDA approval on February 27, 2020, for the acute treatment of migraine and European Commission approval in April 2022 for both acute treatment and prevention. Unlike triptans, which cause vasoconstriction and may be contraindicated in patients with cardiovascular or cerebrovascular disease, oral CGRP receptor antagonists such as rimegepant have not demonstrated vasoconstrictive effects.

Reference:

1. Luo G, Chen L, Conway C M, et al. Discovery of (5 S, 6 S, 9 R)-5-Amino-6-(2, 3-difluorophenyl)-6, 7, 8, 9-tetrahydro-5 H-cyclohepta [b] pyridin-9-yl 4-(2-oxo-2, 3-dihydro-1 H-imidazo [4, 5-b] pyridin-1-yl) piperidine-1-carboxylate (BMS-927711): An Oral Calcitonin Gene-Related Peptide (CGRP) Antagonist in Clinical Trials for Treating Migraine[J]. Journal of medicinal chemistry, 2012, 55(23): 10644-10651.

2. Bigal M E. BMS-927711 for the acute treatment of migraine[J]. Cephalalgia, 2013: 0333102413500728.

3. Kaiyuan Wang, Bo Ni, et al. "Nociceptor neurons promote PDAC progression and cancer pain by interaction with cancer-associated fibroblasts and suppression of natural killer cells." Cell Res. 2025 May;35(5):362-380 PMID: 40122998

4. Lipton RB, Croop R, Stock EG, Stock DA, Morris BA, Frost M, Dubowchik GM, Conway CM, Coric V, Goadsby PJ: Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, for Migraine. N Engl J Med. 2019 Jul 11;381(2):142-149. doi: 10.1056/NEJMoa1811090.