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Purity: ≥98%
Lasmiditan succinate (COL-144, LY-573144) is a novel and selective 5-HT(1F) receptor agonist with Ki of 2.1 nM versus Ki of 1043 nM and 1357 nM at the 5-HT(1B) and 5-HT(1D) receptors, respectively. For the understanding of migraine pathophysiology, it is very important to note that a selective 5-HT(1F) receptor agonist like lasmiditan is effective in the acute treatment of migraine. Thus, migraine can be treated with a drug that has no vasoconstrictor ability. While lasmiditan most likely is effective in the treatment of migraine attacks it had, unfortunately, a high incidence of CNS related AEs in the oral RCT. If confirmed in larger studies in phase III, this might adversely limit the use of this highly specific non-vascular acute treatment of migraine. Larger studies including the parameters of patients' preferences are necessary to accurately position this new treatment principle in relation to the triptans.
| Targets |
Serotonin 1F receptor/5HT1F
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| ln Vitro |
In an in vitro vascular contraction assay using rabbit saphenous vein rings, Lasmiditan did not cause contraction at concentrations up to 100 μM, unlike the 5-HT\(_{1B/1D}\) agonist sumatriptan [2]
Lasmiditan possesses a unique pyridinoyl-piperidine scaffold, a structural class not shared by any other antimigraine therapy. Its distinct chemical structure and pharmacological profile clearly set it apart from the triptan family of drugs. The high potency and selectivity of lasmiditan make it an ideal pharmacological tool to definitively investigate the role of the 5-HT1F receptor in the treatment of migraine headaches. [1] |
| ln Vivo |
In an intravenous, placebo-controlled Phase II clinical trial, migraine patients receiving Lasmiditan doses ranging from 2.5 to 45 mg showed a linear dose-response relationship for headache relief at 2 hours. For the 20 mg dose, the headache relief rate was 64%, compared to 45% for placebo (therapeutic gain 19%) [2].
In an oral, placebo-controlled Phase II trial, Lasmiditan at doses of 50, 100, 200, and 400 mg was superior to placebo for headache relief at 2 hours. For the 400 mg dose, the headache relief rate was 64% versus 25% for placebo (therapeutic gain 38%). The pain-free rate at 2 hours for the 400 mg dose was 28% [2]. In preclinical rodent models relevant to migraine (dural plasma extravasation and c-Fos induction in the trigeminal nucleus caudalis following trigeminal ganglion stimulation), oral administration of Lasmiditan potently inhibited these markers [2] |
| Enzyme Assay |
In vitro binding assays demonstrated that lasmiditan exhibits high affinity for the 5-HT1F receptor, with a Ki value of 2.21 nM, while showing substantially lower affinity for the 5-HT1B and 5-HT1D receptor subtypes (Ki values of 1043 nM and 1357 nM, respectively), representing a selectivity ratio of over 470-fold. Compared to the first-generation 5-HT1F receptor agonist LY334370, lasmiditan displayed superior selectivity for the 5-HT1F receptor relative to other 5-HT1 receptor family members. Notably, unlike the 5-HT1B/1D receptor agonist sumatriptan, lasmiditan did not induce contraction of rabbit saphenous vein rings—a surrogate model for human coronary artery constriction—even at concentrations up to 100 μM. In two preclinical rodent models of migraine, oral administration of lasmiditan potently suppressed markers associated with trigeminal ganglion electrical stimulation, including dural plasma protein extravasation and the induction of the immediate early gene c-Fos in the trigeminal nucleus caudalis. [1]
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| Animal Protocol |
For clinical trials: In the intravenous study, hospitalized patients with moderate or severe migraine were treated with a range of intravenous Lasmiditan doses (2.5–45 mg) or placebo [2].
In the oral study, outpatients with moderate or severe migraine were randomized to receive a single oral dose of Lasmiditan (50, 100, 200, or 400 mg) or placebo [2] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Oral absorption of lasmiditan is quick, with a median tmax of 1.8 hours. An open-label study looking at absorption pharmacokinetics found the Cmax and AUC0-t of lasmiditan following oral administration to be 322.8 ± 122.0 ng/mL and 1892 ± 746.0 ng.h/mL, respectively. The oral bioavailability of lasmiditan has been reported as approximately 40%. Co-administration of lasmiditan with a high-fat meal increased its Cmax and AUC by 22% and 19%, respectively, and delayed Tmax by approximately 1 hour - these differences in absorption are relatively minor and unlikely to be clinically significant. Similarly, severe renal impairment and mild-moderate hepatic impairment were found to increase both AUC and Cmax, but not to a clinically significant extent. Lasmiditan is eliminated primarily via metabolism, with renal excretion accounting for a small fraction of its total elimination. Of the small amount of drug found in the urine post-dose, approximately 66% is comprised of lasmiditan's S-M8 metabolite. Only 3% of an administered dose of lasmiditan was recovered unchanged in the urine, further implying a relatively extensive metabolism of this drug. Lasmiditan has been shown to penetrate the blood-brain barrier. Metabolism / Metabolites The hepatic and extra-hepatic metabolism of lasmiditan is catalyzed primarily by non-CYP enzymes, with ketone reduction appearing to be the primary pathway. While the specific enzymes involved in the metabolism of lasmiditan have not been elucidated, FDA labeling states that the following enzymes are _not_ involved in its metabolism: monoamine oxidases, CYP450 reductase, xanthine oxidase, alcohol dehydrogenase, aldehyde dehydrogenase, and aldo-keto reductases. The metabolites of lasmiditan have not been characterized in published research, but two of its metabolites (M7 and M18) are considered to be pharmacologically inactive. Biological Half-Life The mean elimination half-life of lasmiditan is 5.7 hours. |
| Toxicity/Toxicokinetics |
Hepatotoxicity
In preregistration controlled trials of lasmiditan in several thousand patients, mild-to-moderate serum aminotransferase elevations arose in a small percentage of patients (1% or less) 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 liver injury with symptoms or jaundice attributed to lasmiditan. 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 lasmiditan during breastfeeding. If lasmiditan 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 Lasmiditan exhibits a concentration-independent plasma protein binding of approximately 55-60%. In the intravenous Phase II trial, adverse events were generally mild, reported by 65% of patients on Lasmiditan and 43% on placebo [2] In the oral Phase II trial, treatment-emergent adverse events were reported by 22% of placebo patients and by 65%, 73%, 87%, and 87% of patients receiving 50, 100, 200, and 400 mg of Lasmiditan, respectively. For the 100 mg and 400 mg doses, the majority of adverse events were moderate or severe in intensity. Common adverse events (incidence >5%) included dizziness, fatigue, vertigo, somnolence, paresthesia, heaviness, and nausea [2] |
| References | |
| Additional Infomation |
See also: Lamedittan (with active ingredient).
Drug Indications RAYVOW is indicated for the treatment of acute migraine attacks in adults, with or without aura. |
| Molecular Formula |
C42H42F6N6O8
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| Molecular Weight |
872.82
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| Exact Mass |
872.297
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| CAS # |
439239-92-6
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| Related CAS # |
439239-90-4;613677-28-4 (HCl) 439239-92-6 (succinate) 2171471-98-8 (HCl dihydrate) 2171471-99 (HCl hydrate)
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| PubChem CID |
46927777
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
7.131
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
18
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
62
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| Complexity |
623
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1C=C(C=C(C=1C(NC1=CC=CC(C(C2CCN(C)CC2)=O)=N1)=O)F)F.FC1C=C(C=C(C=1C(NC1=CC=CC(C(C2CCN(C)CC2)=O)=N1)=O)F)F.OC(CCC(=O)O)=O
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| InChi Key |
MSOIHUHNGPOCTH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/2C19H18F3N3O2.C4H6O4/c2*1-25-7-5-11(6-8-25)18(26)15-3-2-4-16(23-15)24-19(27)17-13(21)9-12(20)10-14(17)22;5-3(6)1-2-4(7)8/h2*2-4,9-11H,5-8H2,1H3,(H,23,24,27);1-2H2,(H,5,6)(H,7,8)
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| Chemical Name |
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| 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
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] 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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1457 mL | 5.7286 mL | 11.4571 mL | |
| 5 mM | 0.2291 mL | 1.1457 mL | 2.2914 mL | |
| 10 mM | 0.1146 mL | 0.5729 mL | 1.1457 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04396574 | Recruiting | Drug: Lasmiditan | Migraine | Eli Lilly and Company | June 30, 2020 | Phase 3 |
| NCT04396236 | Recruiting | Drug: Lasmiditan Drug: Placebo |
Migraine | Eli Lilly and Company | June 15, 2020 | Phase 3 |
| NCT05903040 | Recruiting | Drug: Lasmiditan | Migraine Migraine With Aura Migraine Without Aura |
University of Florence | June 15, 2023 | N/A |
| NCT03988088 | Completed | Drug: Lasmiditan | Migraine | Eli Lilly and Company | July 22, 2019 | Phase 1 |
| NCT04881747 | Completed | Drug: Lasmiditan | Healthy | Eli Lilly and Company | May 14, 2021 | Phase 1 |
Proportion of migraine patients with headache relief (a decrease of headache from moderate or severe to none or mild) (HR) at 2h after intravenous lasmiditan (PBOplacebo).J Headache Pain.2012 Jun;13(4):271-5. |
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Proportion of migraine patients with HR at 2h after oral lasmiditan 50–400mg (PBOplacebo).J Headache Pain.2012 Jun;13(4):271-5. |
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