Rimegepant
[CAS# 1289023-67-1]

Identification

• Classification: API >> Other chemicals
• Name: Rimegepant
• Synonyms: BMS 927711; 4-(2,3-Dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-1-yl)-1-piperidinecarboxylic acid (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl ester
• Molecular Formula: C₂₈H₂₈F₂N₆O₃
• Molecular Weight: 534.56
• CAS Registry Number: 1289023-67-1
• EC Number: 880-367-9
• SMILES: C1C[C@H](C2=C(C=CC=N2)[C@H]([C@@H]1C3=C(C(=CC=C3)F)F)N)OC(=O)N4CCC(CC4)N5C6=C(NC5=O)N=CC=C6

Properties

• Solubility: Practically insoluble (0.014 g/L) (25 °C), Calc.^*, 10 mM (DMSO) (Expl)
• Density: 1.45±0.1 g/cm³ (20 °C 760 Torr), Calc.^*
• Index of Refraction: 1.676, Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS08 Warning
• Risk Statements: H361-H361d-H373
• Safety Statements: P203-P260-P280-P318-P319-P405-P501

Discovery and Applications

Rimegepant, a calcitonin gene-related peptide (CGRP) receptor antagonist with the formula C28H28F2N6O3, was developed for the acute and preventive treatment of migraine. The discovery of rimegepant was driven by the understanding that CGRP, a neuropeptide, plays a crucial role in migraine pathophysiology by promoting vasodilation and neurogenic inflammation. Rimegepant was developed by Biohaven Pharmaceuticals and received approval from the U.S. Food and Drug Administration (FDA) in February 2020 for acute migraine treatment and subsequently for preventive use in 2021.

The significance of rimegepant lies in its mechanism of action. As an orally administered small molecule, it blocks the CGRP receptor, preventing CGRP from binding and triggering the cascade of events that lead to migraine attacks. Unlike traditional migraine medications, such as triptans, rimegepant does not constrict blood vessels, making it a safer option for individuals with cardiovascular conditions. This novel mechanism provides an alternative for patients who are unresponsive or intolerant to triptans.

Rimegepant is available in the form of orally disintegrating tablets (ODT), offering convenience and rapid absorption. Its pharmacokinetic profile shows that the drug reaches peak plasma concentrations within 1.5 hours of administration. This quick onset of action is beneficial for treating acute migraine attacks. Clinical trials have demonstrated that a single dose of rimegepant provides significant pain relief within two hours, with effects lasting up to 48 hours for many patients. The drug has also shown efficacy in reducing photophobia, phonophobia, and nausea, which are common migraine symptoms.

In addition to acute treatment, rimegepant has shown promise for migraine prevention. In preventive therapy, regular administration of rimegepant significantly reduces the frequency of migraine days per month. This dual functionality of acute and preventive treatment in one medication represents a significant advancement in migraine management. It offers a streamlined approach for patients who experience both frequent and debilitating migraine episodes.

The development of rimegepant has expanded treatment options for patients suffering from chronic and episodic migraines. Before the advent of CGRP-targeted therapies, many patients relied on drugs with limited efficacy or undesirable side effects. Rimegepant's targeted approach provides a well-tolerated and effective alternative, improving quality of life for migraine sufferers. The safety profile of rimegepant is favorable, with mild adverse effects such as nausea and urinary tract infections reported in clinical trials.

The discovery of rimegepant is part of a broader effort to develop CGRP-based therapies, reflecting advances in the understanding of migraine mechanisms. It has paved the way for further research into CGRP antagonists and their potential in treating other neurological disorders. Rimegepant's success highlights the importance of targeted therapies in addressing unmet medical needs in migraine treatment.

Rimegepant represents a milestone in migraine pharmacotherapy, offering a novel, effective, and well-tolerated option for millions of patients worldwide. Its approval and subsequent clinical adoption underscore the importance of ongoing research into CGRP-related pathways and the potential for innovative treatments to improve patient outcomes.

References

1. Synthesis: Luo, G., et al. (2012). "Discovery of (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (BMS-927711): An orally active, selective CGRP receptor antagonist." Journal of Medicinal Chemistry, 55(23), 10644-10651.
DOI: 10.1021/jm3013147

2. Applications: Croop, R., et al. (2019). "Rimegepant, an oral calcitonin gene-related peptide receptor antagonist, for migraine." New England Journal of Medicine, 381(2), 142-149.
DOI: 10.1056/NEJMoa1811090

3. Review Article: Negro, A., & Martelletti, P. (2020). "Gepants for the acute treatment of migraine: A new therapeutic class." Expert Opinion on Pharmacotherapy, 21(15), 1809-1818.
DOI: 10.1080/14656566.2020.1785429