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Lumateperone (ITI-722; ITI722; Caplyta) is a novel, potent, first-in-class and dual 5HT2A receptor antagonist and dopamine receptor phosphoprotein modulator (DPPM). It is an atypical antipsychotic butyrophenone that was approved in 2019 to treat schizophrenia. It is also being developed for bipolar depression and other neurological indications.
Physicochemical Properties
| Molecular Formula | C24H28FN3O |
| Molecular Weight | 393.497 |
| Exact Mass | 393.221 |
| Elemental Analysis | C, 73.26; H, 7.17; F, 4.83; N, 10.68; O, 4.07 |
| CAS # | 313368-91-1 |
| Related CAS # | Lumateperone tosylate; 1187020-80-9; 313368-91-1 |
| PubChem CID | 21302490 |
| Appearance | Colorless to light yellow ointment |
| Density | 1.3±0.0 g/cm3 |
| Boiling Point | 556.4±0.0 °C at 760 mmHg |
| Flash Point | 290.3±0.0 °C |
| Vapour Pressure | 0.0±0.0 mmHg at 25°C |
| Index of Refraction | 1.646 |
| LogP | 3.39 |
| Hydrogen Bond Donor Count | 0 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 29 |
| Complexity | 593 |
| Defined Atom Stereocenter Count | 2 |
| SMILES | FC1=CC=C(C(CCCN2CC[C@H]3[C@H](C4=CC=CC5=C4N3CCN5C)C2)=O)C=C1 |
| InChi Key | HOIIHACBCFLJET-SFTDATJTSA-N |
| InChi Code | InChI=1S/C24H28FN3O/c1-26-14-15-28-21-11-13-27(16-20(21)19-4-2-5-22(26)24(19)28)12-3-6-23(29)17-7-9-18(25)10-8-17/h2,4-5,7-10,20-21H,3,6,11-16H2,1H3/t20-,21-/m0/s1 |
| Chemical Name | 1-(4-fluorophenyl)-4-[(10R,15S)-4-methyl-1,4,12-triazatetracyclo[7.6.1.05,16.010,15]hexadeca-5,7,9(16)-trien-12-yl]butan-1-one |
| Synonyms | ITI 722; ITI007; ITI722; ITI007; ITI-007; ITI-722 |
| 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 | 5-HT2A receptor (Ki = 0.54 nM) |
| ln Vitro | Lumateperone (2-30 μM) exhibits anti-tumor activity and has the ability to dose-dependently inhibit cell proliferation[1]. |
| ln Vivo | Lumateperone (i.p., 1–10 mg/kg) increases glutamate and dopamine release in rat mPFC slices and promotes NMDA and AMPA-induced currents in a dopamine D1 receptor-dependent manner[2]. |
| Enzyme Assay |
Lumateperone is able to permeate multidrug resistance protein 1 (MDR1) and is very lipophilic at a pH of 7.4, which are characteristics that allow the antipsychotic to be absorbed in the small intestine and the blood brain barrier. Tmax occurs 3-4 hours after oral administration. Lumateperone is extensively metabolized. The carbonyl side chain is reduced by ketone reductase to produce the primary active metabolite. Cytochrome P450 3A4 enzymes metabolize lumateperone to 2 metabolites: the active N-desmethylated carbonyl metabolite (IC200161) or the N-desmethylated alcohol metabolite (IC200565). |
| Animal Protocol |
Adult male Sprague-Dawley rats 1-10 mg/kg Intraperitoneal injection |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Lumateperone is able to permeate multidrug resistance protein 1 (MDR1) and is very lipophilic at a pH of 7.4, which are characteristics that allow the antipsychotic to be absorbed in the small intestine and the blood brain barrier. Tmax occurs 3-4 hours after oral administration. Due to it's molecular weight, virtually all unchanged lumateperone is excreted in the feces. Lumateperone's metabolites are very water soluble which is a property that allows for complete elimination. Approximately 58% of a lumateperone dose can be recovered in the urine, while 29% can be recovered in the feces. The volume of distribution of lumateperone is approximately 4.1 L/Kg after intravenous administration. Lumateperone's clearance is estimated to be 27.9 L/hour. Metabolism / Metabolites Lumateperone is extensively metabolized. The carbonyl side chain is reduced by ketone reductase to produce the primary active metabolite. Cytochrome P450 3A4 enzymes metabolize lumateperone to 2 metabolites: the active N-desmethylated carbonyl metabolite (IC200161) or the N-desmethylated alcohol metabolite (IC200565). Biological Half-Life Lumateperone's half life is reported to be between 13 to 18 hours. The reported half lives of the metabolites ICI200161 and ICI200131, are 20 and 21 hours respectively. |
| Toxicity/Toxicokinetics |
Hepatotoxicity In preregistration controlled trials, ALT elevations arose in 2% of patients receiving lumateperone compared to less than 1% of placebo controls. The elevations, however, were usually mild, transient and typically resolved without dose modification or drug discontinuation. In preregistration trials, there were no instances of severe hepatic adverse events, discontinuations because of liver related events or episodes of clinically apparent liver injury with jaundice. Since its approval and more widescale use, there have been no published reports of liver injury with symptoms or jaundice attributed to lumateperone therapy, but clinical experience with its use has been limited. Likelihood score: E (unlikely cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the clinical use of lumateperone during breastfeeding. However, amounts of lumateperone and its metabolites in breastmilk appear to be low and would not be expected to cause any adverse effects in breastfed infants. If lumateperone is required by the mother, it is not a reason to discontinue breastfeeding ◉ 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 Lumateperone is approximately 97.4% plasma protein bound. |
| References |
[1]. Identification of Trovafloxacin, Ozanimod, and Ozenoxacin as Potent c-Myc G-quadruplex Stabilizers to Suppress c-Myc Transcription and Myeloma Growth. Mol Inform. 2022 Mar 30:e2200011. [2]. Lumateperone-mediated effects on prefrontal glutamatergic receptor-mediated neurotransmission: A dopamine D1 receptor dependent mechanism. Eur Neuropsychopharmacol. 2022 Jul 22;62:22-35. [3]. Lumateperone (https://en.wikipedia.org/wiki/Lumateperone). |
| Additional Infomation |
Schizophrenia is a complex mental illness and impacts approximately 1% of the population. Although there are several antipsychotics including [aripiprazole], [paliperidone] and [clozapine] available for clinical use, they are generally accompanied by significant metabolic and/or neurological adverse effects. Lumateperone is a newly approved 2nd generation antipsychotic currently indicated for the treatment of schizophrenia. It has a unique receptor binding profile and differs from other antipsychotics in that it modulates glutamate, serotonin and dopamine, which are all neurotransmitters that contribute to the pathophysiology of schizophrenia. The data so far indicates that lumateperone can alleviate both positive and negative symptoms of schizophrenia. Further, not only is the new antipsychotic selective for dopamine (D2) receptors in the mesolimbic and mesocortical brain regions, but it also has minimal off-target activity. Both characteristics lend to a more favourable adverse effect profile and ultimately safer drug. Lumateperone is an Atypical Antipsychotic. Lumateperone is a second generation (atypical) antipsychotic agent that is used in the treatment of schizophrenia. Lumateperone is associated with a low rate of serum aminotransferase elevations during therapy, but has not been linked to instances of clinically apparent acute liver injury. See also: Lumateperone Tosylate (is active moiety of). Drug Indication Lumateperone is approved for the treatment of schizophrenia in adults. It is also approved for the treatment of depressive episodes associated with bipolar disorder (i.e. bipolar depression) in adults, as monotherapy and/or adjunctive therapy with lithium or valproate. Mechanism of Action There is much to learn about the pathophysiology of schizophrenia; however, dopamine abnormalities, specifically in the prefrontal and mesolimbic brain regions, are consistent in people with schizophrenia. In addition to dopamine, other neurotransmitters such as serotonin, glutamate, GABA and acetylcholine are thought to play a role. Lumateperone is unique among second generation antipsychotics based on its target profile and dopamine D2 receptor occupancy. Unlike other antipsychotics, lumateperone has partial agonist activity at presynaptic dopamine (D2) receptors, resulting in reduced presynaptic release of dopamine, and antagonistic activity at postsynaptic dopamine (D2) receptors. These characteristics allow lumateperone to efficiently reduce dopamine signaling. Lumateperone also targets dopamine (D1) receptors, and a useful secondary result of D1 activation is increased glutamatergic N-methyl-D-aspartate (NMDA) GluN2B receptor phosphorylation. This is significant since NMDA mediated glutamate signaling appears to be impaired in patients who have schizophrenia. Finally, lumateperone is capable of modulating serotonin by inhibiting serotonin transporters (SERT), and by behaving as a 5-HT2A receptor antagonist. Pharmacodynamics Lumateperone, also known as ITI-007, is an atypical antipsychotic that has proven to be effective in the treatment of schizophrenia. Lumateperone's receptor binding profile is unique, allowing it to target schizophrenia related symptoms while minimizing adverse effects. In contrast to other second generation antipsychotics such as [lurasidone] and [brexpiprazole], lumateperone behaves as a partial agonist and as an antagonist at pre and postynaptic dopamine (D2) receptors respectively. Patients with moderate or severe hepatic impairment (Child-Pugh class B or C) tend to have higher plasma concentrations of lumateperone than those with normal hepatic function. For this reason, patients with moderate or severe hepatic impairment should receive half the recommended daily dosage. |
Solubility Data
| Solubility (In Vitro) |
DMSO: ~79 mg/mL (~200.8 mM) Ethanol: ~79 mg/mL |
| 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 | 2.5413 mL | 12.7065 mL | 25.4130 mL | |
| 5 mM | 0.5083 mL | 2.5413 mL | 5.0826 mL | |
| 10 mM | 0.2541 mL | 1.2706 mL | 2.5413 mL |