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Purity: ≥98%
Lasmiditan (formerly known as COL-144 and 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. The fact that lasmiditan, a selective 5-HT(1F) receptor agonist, works well for treating migraines acutely is crucial information for comprehending the pathophysiology of migraines. Thus, a medication without vasoconstrictor properties can be used to treat migraines. Although lasmiditan is probably useful in treating migraine attacks, the oral RCT unfortunately showed a high rate of CNS-related adverse events. Should this be verified in larger phase III studies, it could negatively restrict the application of this extremely targeted non-vascular acute migraine treatment. To properly place this new treatment principle in relation to the triptans, larger studies that take patient preferences into account are required.
| Targets |
Serotonin 1F receptor/5HT1F; Lasmiditan (also known as COL-144 and LY573144; 2,4,6-trifluoro-N-[6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2yl]benzamide) is a high-affinity, highly selective serotonin (5-HT) 5-HT(1F) receptor agonist.
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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
Lamidetan is rapidly absorbed orally, with a median time to peak concentration (tmax) of 1.8 hours. An open-label study investigating the absorption pharmacokinetics of lamidetan found that after oral administration, its peak plasma concentration (Cmax) and AUC0-t were 322.8 ± 122.0 ng/mL and 1892 ± 746.0 ng·h/mL, respectively. The reported oral bioavailability of lamidetan is approximately 40%. Co-administration with a high-fat meal increased lamidetan's Cmax and AUC by 22% and 19%, respectively, and delayed Tmax by approximately 1 hour—these absorption differences are relatively small and unlikely to be clinically significant. Similarly, severe renal impairment and mild to moderate hepatic impairment increased AUC and Cmax, but not to a clinically significant degree. Lamidetan is primarily eliminated through metabolism, with renal excretion accounting for only a small portion of its total elimination. Of the small amount of drug detected in urine after administration, approximately 66% was the lamiddinan metabolite S-M8. Only 3% of the administered dose was recovered unchanged in the urine, further indicating that the drug is extensively metabolized. Lamiddinan has been shown to cross the blood-brain barrier. Metabolism/Metabolites: Lamiddinan's intrahepatic and extrahepatic metabolism is primarily catalyzed by non-CYP enzymes, with ketone body reduction appearing to be the main metabolic pathway. Although the specific enzymes involved in lamiddinan metabolism have not been identified, the FDA label indicates that the following enzymes are not involved in its metabolism: monoamine oxidase, CYP450 reductase, xanthine oxidase, alcohol dehydrogenase, aldehyde dehydrogenase, and aldehyde-ketone reductase. Published studies have not characterized lamiddinan metabolites, but two of its metabolites (M7 and M18) are considered to be pharmacologically inactive. Biological Half-Life: The mean elimination half-life of lamiddinan is 5.7 hours. |
| Toxicity/Toxicokinetics |
Hepatotoxicity
In pre-registration controlled trials of lasmidettan in thousands of patients, only a small number (1% or less) experienced mild to moderate elevations in serum transaminases, with an overall incidence similar to the placebo group. No reports of symptomatic liver injury or jaundice caused by lasmidettan have been observed in controlled trials or subsequent routine use. Probability score: E (unlikely a cause of clinically apparent acute liver injury). Use during Pregnancy and Lactation ◉ Overview of Use During Lactation There is currently no published experience regarding the use of lasmidettan during lactation. If a mother of an older infant requires lasmidettan, this is not a reason to discontinue breastfeeding, but alternative medications may be preferred until more data are available, especially when breastfeeding newborns or premature infants. ◉ Effects on Breastfed Infants No relevant published information was found as of the revision date. ◉ Effects on Lactation and Breast Milk No relevant published information was found as of the revision date. Protein binding The plasma protein binding rate of lamidutane is approximately 55-60%, and is concentration-independent. In the intravenous phase II trial, adverse events were generally mild, with 65% of patients in the lamidutane group reporting adverse events compared to 43% in the placebo group[2]. In the oral phase II trial, 22% of patients in the placebo group reported adverse events during treatment, compared to 65%, 73%, 87%, and 100% in the lamidutane group, respectively. Adverse reactions occurred in 87% of patients who received 50, 100, 200, and 400 mg lamidutane, respectively. In the 100 mg and 400 mg dose groups, most adverse reactions were moderate or severe. Common adverse reactions (incidence >5%) included dizziness, fatigue, vertigo, somnolence, paresthesia, heaviness, and nausea[2]. |
| References | |
| Additional Infomation |
Pharmacodynamics
Lamidetan is a novel class of acute migraine medications that work by inhibiting neuronal firing rather than constricting cerebral arteries. Lamidetan has a rapid onset of action (a key characteristic of acute migraine treatment), with some patients experiencing relief within 20 minutes. Because it can cause central nervous system depression (e.g., drowsiness, dizziness), lamidetan may lead to severe impaired driving ability; therefore, patients are advised to avoid activities requiring mental concentration for at least 8 hours after taking the medication. Lamidetan may have some abuse potential and should be used with caution in patients at risk of drug abuse—the DEA is currently reviewing its classification as a controlled substance. The safety of lamidetan during pregnancy is not well understood; Eli Lilly is currently monitoring it through a pregnancy exposure registry system. Lamidetan is a novel non-vascular treatment for acute migraines. It is a selective 5-HT1F receptor agonist and does not have vasoconstrictive effects, unlike triptans (5-HT1B/1D agonists). Its efficacy supports treatment of migraine attacks through neural mechanisms. However, the high incidence of central nervous system-related adverse events (such as dizziness and vertigo) observed in oral trials may limit its clinical application if confirmed in larger phase III studies [2]. |
| Molecular Formula |
C19H18F3N3O2
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| Molecular Weight |
377.38
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| Exact Mass |
377.135
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| CAS # |
439239-90-4
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| Related CAS # |
439239-92-6; 613677-28-4; 439239-90-4
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| PubChem CID |
11610526
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
433.3±45.0 °C at 760 mmHg
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| Flash Point |
215.9±28.7 °C
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| Vapour Pressure |
0.0±1.0 mmHg at 25°C
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| Index of Refraction |
1.585
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| LogP |
1.9
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
27
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| Complexity |
530
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1C([H])=C(C([H])=C(C=1C(N([H])C1=C([H])C([H])=C([H])C(C(C2([H])C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C2([H])[H])=O)=N1)=O)F)F
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| InChi Key |
XEDHVZKDSYZQBF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H18F3N3O2/c1-25-7-5-11(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/h2-4,9-11H,5-8H2,1H3,(H,23,24,27)
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| Chemical Name |
2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl]benzamide
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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 | 2.6498 mL | 13.2492 mL | 26.4985 mL | |
| 5 mM | 0.5300 mL | 2.6498 mL | 5.2997 mL | |
| 10 mM | 0.2650 mL | 1.3249 mL | 2.6498 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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