Zavegepant
[CAS# 1337918-83-8]

Identification

• Classification: Biochemical >> Inhibitor >> Endocrinology & hormones >> GPR antagonist
• Name: Zavegepant
• Synonyms: N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-1-oxopropan-2-yl]-4-(2-oxo-1H-quinolin-3-yl)piperidine-1-carboxamide
• Molecular Formula: C₃₆H₄₆N₈O₃
• Molecular Weight: 638.80
• CAS Registry Number: 1337918-83-8
• SMILES: CC1=CC(=CC2=C1NN=C2)C[C@H](C(=O)N3CCN(CC3)C4CCN(CC4)C)NC(=O)N5CCC(CC5)C6=CC7=CC=CC=C7NC6=O

Properties

• Density: 1.3±0.1 g/cm³, Calc.^*
• Index of Refraction: 1.648, Calc.^*
• Boiling Point: 933.7±65.0 °C (760 mmHg), Calc.^*
• Flash Point: 518.5±34.3 °C, Calc.^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319
• Safety Statements: P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330

Discovery and Applications

Zavegepant, chemically known as (S)-3-Amino-3-(4-chlorophenyl)propionic acid, is a drug that has attracted considerable attention for its role in the treatment of migraines. It is a selective calcitonin gene-related peptide (CGRP) receptor antagonist, designed to target the underlying mechanisms of migraines. Migraines are complex neurological events, and CGRP plays a pivotal role in their development by promoting vasodilation and neuroinflammation. Zavegepant was developed to block the action of CGRP, which helps to prevent or alleviate migraine symptoms, offering a targeted therapeutic approach that differs from conventional treatments.

The discovery of Zavegepant stems from the growing understanding of the CGRP pathway in migraine pathophysiology. CGRP is released during a migraine attack, leading to the dilation of blood vessels in the brain, which contributes to the pain and other symptoms associated with migraines. Inhibition of CGRP or its receptor has proven to be an effective strategy in migraine treatment. Zavegepant, specifically, was developed as a nasal spray, allowing for rapid absorption and a quick onset of action. This makes it particularly useful for acute migraine attacks, providing patients with fast relief from pain and discomfort.

Zavegepant has been extensively studied in clinical trials, demonstrating its efficacy and safety. In a phase 2 clinical trial, the drug showed significant improvements in reducing migraine pain and symptoms when compared to a placebo. Its rapid onset of action and favorable safety profile make it an attractive option for patients who seek relief from migraine attacks without the side effects often associated with traditional pain medications. Zavegepant’s ability to target the root cause of migraines, rather than simply masking symptoms, represents a major advancement in migraine therapy.

Beyond its primary use for migraine relief, there is ongoing research into other potential applications of CGRP receptor antagonists like Zavegepant. Researchers are exploring their use in the treatment of other neurovascular disorders, including cluster headaches and certain types of chronic pain. By targeting the CGRP pathway, Zavegepant and similar drugs may offer new therapeutic options for a range of pain-related conditions.

Zavegepant exemplifies a shift in the treatment of neurological disorders, with a focus on precision medicine that targets the underlying causes of disease. Its development is a testament to the progress made in understanding the molecular mechanisms behind migraines and the potential for more effective, targeted treatments. As research continues, Zavegepant may play an even larger role in the future of migraine and pain management.

References

2013. Discovery of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (BMS-742413): A potent human CGRP antagonist with superior safety profile for the treatment of migraine through intranasal delivery. Bioorganic & Medicinal Chemistry Letters, 23(11).
DOI: 10.1016/j.bmcl.2013.04.012

2021. Azepino-indazoles as calcitonin gene-related peptide (CGRP) receptor antagonists. Bioorganic & Medicinal Chemistry Letters, 30(2).
DOI: 10.1016/j.bmcl.2020.127624

2023. Zavegepant: First Approval. Drugs, 83(9).
DOI: 10.1007/s40265-023-01885-6