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LML134 is a novel, orally bioactive and highly selective Histamine 3 receptor (H3R) inverse agonist with Kis of 0.3 nM and 12 nM for hH3R cAMP and hH3R bdg. LML134 penetrates the brain rapidly, leading to high H3R occupancy, and disengages its target with a fast kinetic profile. LML134 has the potential for excessive sleep disorders.
| Targets |
H3 receptor
LML134 targets the histamine H3 receptor (H3R) as an inverse agonist. In a cAMP functional assay, its Ki is 0.3 nM; in a radioligand binding assay using [³H]‑N‑α‑methylhistamine, its Ki is 126 nM (values from Table 1, reported as cAMP/binding Ki). It shows no significant activity against histamine H1, H2, or H4 receptors (all IC₅₀ > 30 μM) and does not bind to 137 other pharmacology/safety targets (all IC₅₀ > 30 μM).[1] |
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| ln Vitro |
LML134 displays excellent drug‑like properties: water solubility of 95 μM at pH 6.8, and high permeability with an apparent permeability coefficient (Pₐₚₚ) of 19.0 × 10⁻⁶ cm/s in MDCK‑MDR1 cells, with an efflux ratio of 1.28, indicating no active efflux and good brain penetration potential. It does not inhibit cytochrome P450 enzymes at 10 μM (CYP3A4 midazolam: 12% inhibition; CYP3A4 testosterone: 25%; CYP2C9: 0%; CYP2D6: 5%; CYP1A2: 8%; CYP2C19: 0%). It is inactive in a phospholipidosis induction assay and negative in both Ames and micronucleus genotoxicity assays. In rat liver microsomes, exposure for 30 min leads to three main metabolites: N‑dealkylation to 18a and 20, and N‑oxidation to 21; the active metabolite 18a has lower brain penetration and slower receptor disengagement.[1]
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| ln Vivo |
LML134 (compound 18b) (oral; 10 mg/kg) in male Sprague-Dawley rats shows fast oral absorption with a Tmax of 0.5 hours, t1/2 of 1.54 hours, and a fraction absorbed of 44%[1]. It also shows rapid clearance.[1]
LML134 (i.v.; 1 mg/kg) causes low plasma protein binding (Fu = 39.0%) and has a t1/2 of 0.44 hours and a CL of 28 mL/min/kg in male Sprague-Dawley rat.[1] In male Sprague‑Dawley rats, oral administration of LML134 at 10 mg/kg results in rapid brain penetration and high H3 receptor occupancy (RO): 89% at 0.5 h, 90% at 1 h, and only 17% at 6 h post‑dose (ex vivo radioligand binding assay). The compound increases brain tele‑methylhistamine (tMeHA) concentration by 768% at 1 h compared to vehicle, indicating effective target engagement and enhanced histaminergic neurotransmission. Compared to bavisant, which still shows 50% RO at 5 h, LML134 shows a faster receptor disengagement (≈20% RO at 5 h). A full time‑course of RO confirms rapid onset and offset consistent with a low potential for mechanism‑related insomnia.[1] |
| Enzyme Assay |
LML134 affinity for H3R was determined using a [³H]‑N‑α‑methylhistamine radioligand binding assay on human H3 receptor membranes. The binding Ki was calculated from competition binding experiments. Functional inverse agonist activity was assessed via a cAMP assay (adenylate cyclase) measuring the inhibition of forskolin‑stimulated cAMP accumulation in cells expressing the human H3 receptor. The cAMP Ki value was derived from concentration‑response curves. Both assays were performed with 2‑3 samples per concentration, and the reported Ki values are 126 nM (binding) and 0.3 nM (cAMP).[1]
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| Cell Assay |
The permeability of LML134 was evaluated in MDCK‑MDR1 cells (Madin‑Darby canine kidney cells transfected with the human multidrug resistance gene). Cells were grown on permeable supports, and the apparent permeability (Pₐₚₚ) was measured in the apical‑to‑basolateral direction. The compound showed a Pₐₚₚ of 19.0 × 10⁻⁶ cm/s and an efflux ratio of 1.28, indicating good passive permeability and no significant efflux. Solubility was determined using a high‑throughput equilibrium shake‑flask method at pH 6.8 followed by HPLC analysis, giving a value of 95 μM.[1]
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| Animal Protocol |
All animal studies were performed in male Sprague‑Dawley rats. For pharmacokinetic (PK) and pharmacodynamic (PD) assessments, LML134 was administered orally at 10 mg/kg or intravenously at 1 mg/kg. Blood samples and frontal cortex (for brain concentration and receptor occupancy) were collected at various time points (e.g., 0.5, 1, 6 h post‑dose). Receptor occupancy (RO) was determined ex vivo by incubating brain homogenates with [³H]‑N‑α‑methylhistamine and measuring specific binding. Tele‑methylhistamine (tMeHA) brain levels were measured as a biomarker of H3R engagement. For microsomal metabolism studies, rat liver microsomes were incubated with the compound for 30 min to identify metabolites. All procedures were carried out according to protocols detailed in a previous article (reference 14 of the paper).[1]
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| ADME/Pharmacokinetics |
In male Sprague‑Dawley rats, LML134 shows rapid oral absorption with Tₘₐₓ = 0.5 h and an oral fraction absorbed (F) of 44%. After intravenous administration (1 mg/kg), the compound exhibits a terminal half‑life (T₁/₂) of 0.44 h, total blood clearance (CL) of 28 mL/min/kg, volume of distribution at steady state (Vₛₛ) of 0.79 L/kg, AUC (extrapolated to infinity) of 601 h·ng/mL, and mean residence time (MRT) of 0.47 h. The brain‑to‑plasma concentration ratio 1 h after oral dosing is 0.93. Plasma protein binding is low: unbound fraction (Fᵤ) = 39.0% in rat, 57.6% in dog, and 33.6% in human plasma. The compound shows good permeability (Pₐₚₚ = 19.0 × 10⁻⁶ cm/s in MDCK‑MDR1) and no efflux.[1]
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| Toxicity/Toxicokinetics |
LML134 does not inhibit hERG channels at concentrations up to 10 μM (no significant hERG binding). In a panel of 137 targets including histamine H1, H2, H4 receptors, all IC₅₀ values are > 30 μM, confirming high selectivity. The compound shows no inhibition of cytochrome P450 enzymes at 10 μM (CYP3A4 midazolam: 12%; CYP3A4 testosterone: 25%; CYP2C9: 0%; CYP2D6: 5%; CYP1A2: 8%; CYP2C19: 0%). It is inactive in a phospholipidosis induction assay and negative in both the Ames bacterial reverse mutation test and the in vitro micronucleus genotoxicity assay. Plasma protein binding is low across species (rat Fᵤ = 39.0%, dog 57.6%, human 33.6%).[1]
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| References | |
| Additional Infomation |
LML134 is a histamine H3 receptor inverse agonist under clinical investigation for excessive sleep disorders, including narcolepsy and shift work disorder. It was designed to achieve rapid receptor engagement (high H3R occupancy >80%) and fast disengagement (residual occupancy <20% at 6 h in rats) to provide wakefulness‑promoting effects without causing insomnia on the following night—a side effect that plagued earlier H3R inverse agonists such as pitolisant (plasma half‑life ~11 h in humans). The compound completed a Phase I study (NCT02334449) to assess safety, tolerability, and pharmacokinetics in healthy volunteers. It is currently undergoing further clinical studies (e.g., NCT03141086) to evaluate its wakefulness‑promoting effect in shift work disorder. The mechanism of action involves inverse agonism at presynaptic H3 autoreceptors, which reduces feedback inhibition of histamine release, thereby increasing synaptic histamine levels and compensating for the weak orexin signal in narcolepsy patients.[1]
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| Molecular Formula |
C19H29N5O3
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|---|---|
| Molecular Weight |
375.465264081955
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| Exact Mass |
375.23
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| Elemental Analysis |
C, 60.78 H, 7.79 N, 18.65 O, 12.78
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| CAS # |
1542135-76-1
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| PubChem CID |
72948400
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
0.6
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
27
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| Complexity |
629
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CN1C(=O)C=CC(=N1)N2CCC(CC2)OC(=O)N3CCN(CC3)C4CCC4
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| InChi Key |
BVUJMFFRMZRNAT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H29N5O3/c1-21-18(25)6-5-17(20-21)23-9-7-16(8-10-23)27-19(26)24-13-11-22(12-14-24)15-3-2-4-15/h5-6,15-16H,2-4,7-14H2,1H3
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| Chemical Name |
[1-(1-methyl-6-oxopyridazin-3-yl)piperidin-4-yl] 4-cyclobutylpiperazine-1-carboxylate
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| Synonyms |
LML-134; LML 134; LML134
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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 |
| 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) |
DMSO: ~12.5 mg/mL (~33.3 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (3.33 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1.25 mg/mL (3.33 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: ≥ 1.25 mg/mL (3.33 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6633 mL | 13.3166 mL | 26.6333 mL | |
| 5 mM | 0.5327 mL | 2.6633 mL | 5.3267 mL | |
| 10 mM | 0.2663 mL | 1.3317 mL | 2.6633 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.
Link: https://clinicaltrials.gov/ct2/show/NCT03141086
Conditions:Circadian Rhythm DisordersLink: https://clinicaltrials.gov/ct2/show/NCT02334449
Conditions:Healthy VolunteersProducts are for research use only; We do not sell to patients
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