CGRP (calcitonin gene-related peptide) receptor

Zavegepant is a small molecule inhibitor of the calcitonin gene-related peptide (CGRP) receptor that blocks the action of CGRP, a potent vasodilator believed to play a role in migraine headaches. Zavegepant is a highly soluble small molecule calcitonin gene related peptide (CGRP) receptor antagonist, with potential analgesic and immunomodulating activities.

Zavegepant is a calcitonin gene-related peptide (CGRP) receptor antagonist used for the acute treatment of migraine. The pathophysiology of migraine has not been fully elucidated; however, specific vasoactive substances and neurotransmitters such as CGRP, neurokinin A, nitric oxide, and substance P may participate in the neurovascular and cortical spreading depression mechanisms. In acute migraine, the release of CGRP increases vasodilation and modulates neuronal excitability, which facilitates pain responses in structures for migraine pain transmission, such as the trigeminal system. Therefore, CGRP receptor antagonists such as zavegepant inhibit vasodilation mechanisms and desensitize neuronal circuits.
The relationship between the pharmacodynamic activity of zavegepant and its mechanism of action is unclear. No clinically relevant differences were detected when comparing the resting blood pressure of healthy volunteers given sumatriptan and zavegepant concomitantly to those given sumatriptan alone. Using zavegepant leads to a clinically relevant QT interval prolongation at a dose up to 4 times the recommended daily dose. The use of zavegepant may cause hypersensitivity reactions, such as facial swelling and urticaria. If a hypersensitivity reaction occurs, the product label recommends discontinuing zavegepant and initiating appropriate therapy.
Zavegepant is a member of the class of ureas that is urea in which both amino groups are replaced by 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl and {(2R)-3-(7-methyl-1H-indazol-5-yl)-1-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-1-oxopropan-2-yl}amino groups. It is a calcitonin gene-related peptide receptor antagonist whose hydrochloride salt has been approved by the FDA for the acute treatment of migraine. It has a role as a calcitonin gene-related peptide receptor antagonist. It is a quinolone, a piperidinecarboxamide, a member of ureas, a N-acylpiperazine, a member of piperidines and a member of indazoles. It is a conjugate base of a zavegepant(1+).
Zavegepant (BHV-3500) is a calcitonin gene-related peptide (CGRP) receptor antagonist. CGRP is released from sensory nerves and acts as a strong vasodilator, and thanks to these properties, it is involved in pain pathways. CGRP receptors are expressed in the central and peripheral nervous system; however, CGRP does not cross the blood-brain barrier, suggesting that it acts on peripheral nerves. In migraine, CGRP innervates pain-producing meningeal blood vessels and is released by trigeminal nerve stimulation. Since they inhibit these mechanisms and desensitize neuronal circuits, the use of CGRP receptor antagonists is beneficial in the treatment of migraine. Small molecule CGRP antagonists are also known as "gepants", and this category includes other drugs such as [rimegepant] and [ubrogepant]. Zavegepant is a third-generation CGRP receptor antagonist that is small in size and highly soluble. Due to its pharmacological properties, it can be administered intranasally. In March 2023, the FDA approved the use of zavegepant nasal spray for the acute treatment of migraine with or without aura in adults. A clinical trial (NCT04804033) is currently investigating the efficacy and safety of oral zavegepant in migraine prevention, and another one (NCT04987944) is evaluating the safety and efficacy of oral zavegepant (150 mg bid) in subjects with mild allergic asthma.

Zavegepant is a Calcitonin Gene-related Peptide Receptor Antagonist. The mechanism of action of zavegepant is as a Calcitonin Gene-related Peptide Receptor Antagonist.
Zavegepant is a small molecule inhibitor of the calcitonin gene-related peptide (CGRP) receptor that blocks the action of CGRP, a potent vasodilator believed to play a role in migraine headaches. Zavegepant is provided as a nasal spray and is approved for treatment of acute migraine attacks. In clinical trials, zavegepant was generally well tolerated with only rare instances of transient serum aminotransferase elevations during therapy and with no reported instances of clinically apparent liver injury.
Zavegepant is a highly soluble small molecule calcitonin gene related peptide (CGRP) receptor antagonist, with potential analgesic and immunomodulating activities. Upon administration, zavegepant targets, binds to and inhibits the activity of CGRP receptors located on mast cells in the brain. This may inhibit neurogenic inflammation caused by trigeminal nerve release of CGRP. In addition, by blocking the CGRP receptors located in smooth muscle cells within vessel walls, zavegepant inhibits the pathologic dilation of intracranial arteries. Zavegepant, by blocking the CGRP receptors, also suppresses the transmission of pain by inhibiting the central relay of pain signals from the trigeminal nerve to the caudal trigeminal nucleus. Altogether, this may relieve migraine. As CGRP receptors induce the release of pro-inflammatory mediators, such as interleukin-6 (IL-6), from inflammatory cells, zavegepant may prevent an IL-6-mediated inflammatory response. Zavegepant may also inhibit the CGRP-mediated induction of eosinophil migration and the stimulation of beta-integrin-mediated T cell adhesion to fibronectin at the site of inflammation, and may abrogate the CGRP-mediated polarization of the T cell response towards the pro-inflammatory state characterized by Th17 and IL-17. This may improve lung inflammation and oxygenation, prevent edema, and further lung injury. CGRP, a 37 amino-acid peptide expressed in and released from a subset of polymodal primary sensory neurons of the trigeminal ganglion and nerve fibers projecting to the airways and by pulmonary neuroendocrine cells, plays an important role in pain transmission, inflammation, and neurogenic vasodilatation. It is released upon acute lung injury and upregulation of transient receptor potential (TRP) channels.
ZAVEGEPANT is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 2023 and is indicated for migraine disorder and has 3 investigational indications.

Absorption, Distribution and Excretion
Peak plasma concentrations were detected approximately 30 minutes after a single intranasal administration of zavigipam (10 mg). The absolute bioavailability of zavigipam administered via nasal spray is approximately 5%. At single intranasal doses up to 40 mg (4 times the recommended dose of 10 mg), the pharmacokinetics of zavigipam were slightly lower than dose-proportionation. No drug accumulation was observed after 14 days of once-daily administration of zavigipam. Compared to normal subjects, patients with moderate hepatic impairment (Child-Pugh B) showed increases of 16% and 1.9-fold in Cmax and AUC, respectively; however, based on clinical safety experience and extremely low drug exposure, these changes are not expected to be clinically significant. For subjects with an estimated creatinine clearance (CLcr) ≥ 30 mL/min, the pharmacokinetic differences of zavigipam are not expected to be clinically significant. Increased exposure to zavigipam may be observed in patients with CLcr between 15 and 29 mL/min.
Zavegepant is primarily excreted via the bile/fecal route, with the renal route playing a minor role in its clearance. Following a single intravenous injection of 5 mg [14C]-zavegepant in healthy male subjects, approximately 80% and 11% of the dose were recovered unchanged in feces and urine, respectively.
The mean apparent volume of distribution of intranasally administered zavegepant was approximately 1774 L.
The mean apparent clearance of intranasally administered zavegepant was 266 L/h.

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Metabolism/Metabolites
In vitro studies have shown that zavegepant is primarily metabolized by CYP3A4, with less metabolic activity by CYP2D6. Approximately 90% of the circulating dose of [14C]-zavegepant (5 mg) following a single intravenous injection was unchanged. No more than 10% of zavegepant metabolites were detected in plasma (no major metabolites).

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Biological Half-Life
After intranasal administration of 10 mg, the effective half-life of zavigipan is 6.55 hours.

Hepatotoxicity
In a pre-registration controlled trial of zavegepant in thousands of patients, only a small number (1% to 2%) experienced mild to moderate elevations in serum transaminases, with an overall incidence similar to the placebo group. No clinically significant liver injury caused by zavegepant has been reported in the controlled trial or subsequent routine use. In contrast, telcagepant, an oral CGRP receptor antagonist initially used to treat migraines, was discontinued due to several cases of clinically significant liver injury during treatment. These liver injuries manifested as significantly elevated serum transaminase levels and symptoms such as fatigue, nausea, and abdominal discomfort within 2 to 4 weeks of starting treatment. These symptoms resolved rapidly upon discontinuation of treatment. No similar events have been reported with zavegepant.
Probability Score: E (Unlikely to cause clinically significant acute liver injury).
Effects during Pregnancy and Lactation

◉ Overview of Use During Lactation
There is currently no published experience regarding the use of zavegepant during lactation. Zavipan has a protein binding rate of 90%, therefore the drug concentration in breast milk may be low. If a mother of an older infant needs to use zavipan, this is not a reason to stop breastfeeding, but until more data is available, it is recommended to prioritize other medications, especially when breastfeeding newborns or premature infants.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
Zavipan has a plasma protein binding rate of approximately 90%.

J Med Chem . 2020 Jul 9;63(13):6600-6623.

Pharmacodynamics
The relationship between the pharmacodynamic activity and mechanism of action of zavigepan is unclear. No clinically significant difference was found in resting blood pressure in healthy volunteers taking sumatriptan and zavigepan concurrently versus those taking sumatriptan alone. Zavigepan use can cause QT interval prolongation at doses up to four times the recommended daily dose, and this has been clinically significant. Zavigepan use may cause hypersensitivity reactions, such as facial swelling and urticaria. If a hypersensitivity reaction occurs, the product information leaflet recommends discontinuing zavigepan and initiating appropriate treatment. Calciotonin gene-related peptide (CGRP) The crucial role of CGRP in the pathophysiology of migraine was discovered more than 30 years ago, but successful clinical development of targeted therapy has only recently been achieved. This article reviews the development of medicinal chemistry over the past few decades, which has been crucial to advancing the development of small molecule CGRP receptor antagonists (also known as gepimbrine), including currently clinically used drugs such as remipimbrine, wazepimbrine, ubrogpimbrine, and atorgipam. Achieving clinically effective CGRP signaling blockade requires overcoming many challenges, such as: overcoming ligands with sub-nanomolar affinity for the receptor; designing antagonists with extended conformations and multiple pharmacophores while maintaining their solubility and oral bioavailability; and achieving circulating free plasma concentrations close to maximum CGRP receptor coverage. This article describes the clinical efficacy of oral and intranasal gepimbrine and injectable CGRP monoclonal antibodies (mAbs), as well as the latest synthetic advances benefiting from the latest structural biology data. The recent approval of the first oral gepimbrine marks a new era in migraine treatment. [1]

C36H46N8O3

638.817

638.369

C, 67.69; H, 7.26; N, 17.54; O, 7.51

1337918-83-8

1414976-20-7 (HCl);1337918-83-8;

53472683

White to off-white solid powder

1.3±0.1 g/cm3

933.7±65.0 °C at 760 mmHg

518.5±34.3 °C

0.0±0.3 mmHg at 25°C

1.648

4.3

3

6

6

47

1160

1

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

JJVAPHYEOZSKJZ-JGCGQSQUSA-N

InChI=1S/C36H46N8O3/c1-24-19-25(20-28-23-37-40-33(24)28)21-32(35(46)43-17-15-42(16-18-43)29-9-11-41(2)12-10-29)39-36(47)44-13-7-26(8-14-44)30-22-27-5-3-4-6-31(27)38-34(30)45/h3-6,19-20,22-23,26,29,32H,7-18,21H2,1-2H3,(H,37,40)(H,38,45)(H,39,47)/t32-/m1/s1

(R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide

Zavzpret; Vazegepant; BMS 742413; 1337918-83-8; BMS-742,413; BHV-3500; BMS-742413; BHV 3500; BMS742413; BHV3500

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)