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Zavegepant (Vazegepant; BHV-3500; Zavzpret; BMS 742413), CGRP receptor antagonist that has been approved in Feb 2023 by FDA for treating migraine.
Physicochemical Properties
| Molecular Formula | C36H46N8O3 |
| Molecular Weight | 638.817 |
| Exact Mass | 638.369 |
| Elemental Analysis | C, 67.69; H, 7.26; N, 17.54; O, 7.51 |
| CAS # | 1337918-83-8 |
| Related CAS # | 1414976-20-7 (HCl);1337918-83-8; |
| PubChem CID | 53472683 |
| Appearance | White to off-white solid powder |
| Density | 1.3±0.1 g/cm3 |
| Boiling Point | 933.7±65.0 °C at 760 mmHg |
| Flash Point | 518.5±34.3 °C |
| Vapour Pressure | 0.0±0.3 mmHg at 25°C |
| Index of Refraction | 1.648 |
| LogP | 4.3 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 6 |
| Heavy Atom Count | 47 |
| Complexity | 1160 |
| Defined Atom Stereocenter Count | 1 |
| 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 |
| InChi Key | JJVAPHYEOZSKJZ-JGCGQSQUSA-N |
| InChi Code | 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 |
| Chemical Name | (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 |
| Synonyms | Zavzpret; Vazegepant; BMS 742413; 1337918-83-8; BMS-742,413; BHV-3500; BMS-742413; BHV 3500; BMS742413; BHV3500 |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | CGRP (calcitonin gene-related peptide) receptor |
| ln Vitro | 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. |
| ln Vivo |
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. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion After a single intranasal dose of zavegepant (10 mg), the peak plasma concentration was detected approximately 30 minutes later. The absolute bioavailability of zavegepant administered with a nasal spray is approximately 5%. Up to 40 mg (4 times the recommended dose of 10 mg), a single intranasal dose of zavegepant has slightly less than dose-proportional pharmacokinetics. There was no evidence of zavegepant accumulation with once-a-day zavegepant taken for 14 days. Compared to normal subjects, patients with moderate hepatic impairment (Child-Pugh B) have a Cmax and AUC 16% and 1.9-fold higher, respectively; however, these changes are not expected to be clinically significant based on clinical safety experience and minimal accumulation of drug exposures. In subjects with estimated creatinine clearance (CLcr) greater or equal to 30 mL/min, the differences in zavegepant pharmacokinetics are not expected to be clinically significant. In patients with a CLcr from 15 to 29 mL/min, zavegepant exposure may increase. Zavegepant is mainly excreted via the biliary/fecal route, while the renal route plays a minor role in its elimination. In healthy male subjects given a single dose of 5 mg [14C]-zavegepant intravenously, approximately 80% and 11% of the dose were recovered as unchanged zavegepant in feces and urine, respectively. Intranasal zavegepant has a mean apparent volume of distribution of approximately 1774 L. Intranasal zavegepant has a mean apparent clearance of 266 L/h. Metabolism / Metabolites _In vitro_, zavegepant is mainly metabolized by CYP3A4, and by CYP2D6 to a lesser extent. After a single intravenous dose of [14C]-zavegepant (5 mg), approximately 90% of the circulating dose was unchanged zavegepant. None of the zavegepant metabolites detected in plasma were found at a proportion higher than 10% (no major metabolites). Biological Half-Life Following a 10 mg dose, intranasal zavegepant has an effective half-life of 6.55 hours. |
| Toxicity/Toxicokinetics |
Hepatotoxicity
In preregistration, controlled trials of zavegepant in several thousand patients, mild-to-moderate serum aminotransferase elevations arose in a small percentage of patients (1% to 2%) and overall rates were not different from those in placebo recipients. In the controlled trials and subsequently with general use, there have been no reports of clinically apparent liver injury attributed to zavegepant. In contrast, telcagepant, the initial oral CGRP receptor antagonist evaluated as therapy for migraine headaches, was abandoned during development because of several instances of clinically apparent liver injury in recipients that was characterized by marked elevations in serum aminotransferase levels and symptoms of fatigue, nausea and abdominal discomfort arising within 2 to 4 weeks of starting therapy. Such events rapidly resolved with prompt stopping of therapy. Similar episodes have not been reported with zavegepant. Likelihood score: E (unlikely cause of clinically apparent acute liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation There is no published experience with zavegepant during breastfeeding. Zavegepant is 90% protein bound, so levels in milk are likely low. If zavegepant is required by the mother of an older infant, it is not a reason to discontinue breastfeeding, but until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Zavegepant has a plasma protein binding of approximately 90%. |
| References | J Med Chem . 2020 Jul 9;63(13):6600-6623. |
| Additional Infomation |
Pharmacodynamics 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. The pivotal role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology was identified over 30 years ago, but the successful clinical development of targeted therapies has only recently been realized. This Perspective traces the decades long evolution of medicinal chemistry required to advance small molecule CGRP receptor antagonists, also called gepants, including the current clinical agents rimegepant, vazegepant, ubrogepant, and atogepant. Providing clinically effective blockade of CGRP signaling required surmounting multiple challenging hurdles, including defeating a sizable ligand with subnanomolar affinity for its receptor, designing antagonists with an extended confirmation and multiple pharmacophores while retaining solubility and oral bioavailability, and achieving circulating free plasma levels that provided near maximal CGRP receptor coverage. The clinical efficacy of oral and intranasal gepants and the injectable CGRP monoclonal antibodies (mAbs) are described, as are recent synthetic developments that have benefited from new structural biology data. The first oral gepant was recently approved and heralds a new era in the treatment of migraine. [1] |
Solubility Data
| Solubility (In Vitro) | 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 |
| Solubility (In Vivo) |
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. Injection Formulations (e.g. IP/IV/IM/SC) 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). 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) Oral Formulations 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). 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 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5654 mL | 7.8269 mL | 15.6539 mL | |
| 5 mM | 0.3131 mL | 1.5654 mL | 3.1308 mL | |
| 10 mM | 0.1565 mL | 0.7827 mL | 1.5654 mL |