5-HT2A receptor (Ki = 0.54 nM)

Lumateperone (2-30 μM) exhibits anti-tumor activity and has the ability to dose-dependently inhibit cell proliferation[1].

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].

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.

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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).

Adult male Sprague-Dawley rats
1-10 mg/kg
Intraperitoneal injection

Absorption, Distribution and Excretion
Rumatepirozon can cross the multidrug resistance protein 1 (MDR1) and is highly lipophilic at pH 7.4, allowing this antipsychotic drug to be absorbed across the small intestine and blood-brain barrier. Peak time (Tmax) is reached 3–4 hours after oral administration. Due to its small molecular weight, almost all unmetabolized rumatepirozon is excreted in feces. The metabolites of rumatepirozon are highly water-soluble, enabling complete clearance. Approximately 58% of the rumatepirozon dose is recovered in urine and 29% in feces. Following intravenous injection, the volume of distribution of rumatepirozon is approximately 4.1 L/kg. The clearance of rumatepirozon is estimated at 27.9 L/h. Metabolisms/Metabolites Rumatepirozon is extensively metabolized. The carbonyl side chain is reduced by ketone reductase to the major active metabolite. Cytochrome P450 3A4 enzymes metabolize rumatpiron into two metabolites: an active N-demethylcarbonyl metabolite (IC200161) or an N-demethylol metabolite (IC200565).
Biological half-life
The half-life of rumatpiron has been reported to be 13 to 18 hours. The half-lives of metabolites ICI200161 and ICI200131 have been reported to be 20 hours and 21 hours, respectively.

Hepatotoxicity
In pre-registration controlled trials, elevated ALT levels occurred in 2% of patients treated with rumatepone, compared to less than 1% in the placebo group. However, these elevations were usually mild, transient, and typically resolved without dose adjustment or discontinuation. No serious hepatic adverse events, discontinuation due to liver-related events, or clinically significant liver injury with jaundice occurred in the pre-registration trials. Since its approval and widespread use, there have been no published reports of symptomatic or jaundiced liver injury caused by rumatepone treatment, but clinical experience with its use is limited. Probability score: E (unlikely a cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information regarding the clinical use of rumatepone during lactation. However, the levels of rumatepone and its metabolites in breast milk appear to be very low, and no adverse effects are expected on breastfed infants. If the mother needs rumate, this is not a reason to stop breastfeeding.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
The plasma protein binding rate of rumate is approximately 97.4%.

[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).

Schizophrenia is a complex mental illness affecting approximately 1% of the population. While several antipsychotic drugs are currently available for clinical use, including aripiprazole, paliperidone, and clozapine, they are often accompanied by significant metabolic and/or neurological adverse reactions. Rumatepirozon is a newly approved second-generation antipsychotic drug currently used to treat schizophrenia. It possesses unique receptor-binding properties, differing from other antipsychotics in that it modulates glutamate, serotonin, and dopamine—neurotransmitters involved in the pathophysiological processes of schizophrenia. Current data indicate that rumatepirozon can alleviate both positive and negative symptoms of schizophrenia. Furthermore, this novel antipsychotic drug is selective for dopamine (D2) receptors in the mesolimbic system and mesocortical regions, exhibiting minimal off-target effects. Both of these characteristics contribute to a more favorable adverse reaction profile, ultimately making it a safer drug. Rumatepirozon is an atypical antipsychotic. Rumatepirozon is a second-generation (atypical) antipsychotic drug used to treat schizophrenia. The incidence of elevated serum transaminases during rumatepirozon treatment is low, but it has not been found to be associated with clinically significant cases of acute liver injury. See also: rumatepirozon tosylate (its active ingredient). Drug Indications Rumatepirozon is approved for the treatment of schizophrenia in adults. It is also approved for the treatment of depressive episodes associated with bipolar disorder in adults (i.e., bipolar depression), as monotherapy and/or in combination with lithium or valproate. Mechanism of Action Much remains to be learned about the pathophysiology of schizophrenia; however, dopamine abnormalities are prevalent in the brains of patients with schizophrenia, particularly in the prefrontal and mesolimbic regions. In addition to dopamine, other neurotransmitters such as serotonin, glutamate, gamma-aminobutyric acid (GABA), and acetylcholine are also believed to play a role. Rumatepirozon stands out among second-generation antipsychotics due to its target spectrum and dopamine D2 receptor occupancy. Unlike other antipsychotics, rumatepiroron has partial agonist activity against presynaptic dopamine (D2) receptors, thereby reducing presynaptic dopamine release, while also antagonizing postsynaptic dopamine (D2) receptors. These properties allow rumatepiroron to effectively reduce dopamine signaling. Rumatepiroron also targets dopamine (D1) receptors, and a beneficial secondary consequence of D1 receptor activation is increased phosphorylation of glutamatergic N-methyl-D-aspartate (NMDA)GluN2B receptors. This is significant because NMDA-mediated glutamate signaling appears to be impaired in patients with schizophrenia. Furthermore, rumatepiroron can modulate serotonin by inhibiting the serotonin transporter (SERT) and acting as a 5-HT2A receptor antagonist.

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Pharmacodynamics
Rumatepiroron, also known as ITI-007, is an atypical antipsychotic that has been shown to be effective in treating schizophrenia.
Rumatiperone's unique receptor-binding properties allow it to target schizophrenia-related symptoms while minimizing adverse effects. Unlike other second-generation antipsychotics such as lurasidone and birepiperazole, rumatiperone acts as a partial agonist and antagonist of presynaptic and postsynaptic dopamine (D2) receptors, respectively. Plasma rumatiperone concentrations are often higher in patients with moderate or severe hepatic impairment (Child-Pugh B or C) than in patients with normal liver function. Therefore, patients with moderate or severe hepatic impairment should take half the recommended daily dose.

C24H28FN3O

393.497

393.221

C, 73.26; H, 7.17; F, 4.83; N, 10.68; O, 4.07

313368-91-1

Lumateperone tosylate; 1187020-80-9; 313368-91-1

21302490

Colorless to light yellow ointment

1.3±0.0 g/cm3

556.4±0.0 °C at 760 mmHg

290.3±0.0 °C

0.0±0.0 mmHg at 25°C

1.646

3.39

0

5

5

29

593

2

FC1=CC=C(C(CCCN2CC[C@H]3[C@H](C4=CC=CC5=C4N3CCN5C)C2)=O)C=C1

HOIIHACBCFLJET-SFTDATJTSA-N

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

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

ITI 722; ITI007; ITI722; ITI007; ITI-007; ITI-722

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~79 mg/mL (~200.8 mM)
Ethanol: ~79 mg/mL

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.

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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).

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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)

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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).

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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

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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.

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 (Please use freshly prepared in vivo formulations for optimal results.)