JAK1/2

Momelotinib sulfate, also known as CYT387 sulfate salt, suppresses the growth of Ba/F3-JAK2V617F and human erythroleukemia (HEL) cells (IC50=1.5 μM) or Ba/F3-MPLW515L cells (IC50=200 nM). However, it exhibits significantly less activity against K562 cells that harbor BCR-ABL (IC50=58 μM) and MV4-11 cells that harbor FLT3 mutation (IC50=3 μM). With an IC50 value of 1.4 μM, the proliferation of parental Ba/F3 cells (Ba/F3-wt) stimulated with IL-3 is suppressed, in keeping with the known function of IL-3-dependent signaling in the parental cell line[1].

Over the course of eight weeks, momelotinib sulfate (CYT387 sulfate salt), at twice the dose employed in the illness model (50 and 100 mg/kg), has little to no effect on peripheral blood counts. With a half-life of roughly two hours, the median plasma peak concentrations are 7.1 μM for the lower dose and 32.1 μM for the higher dose. Twelve-hour trough values for the 25 mg/kg and 50 mg/kg doses, respectively, are 10nM and 900nM. The cohort's average white blood cell counts and hematocrit values at day 34 post-transplantation were more than one standard deviation above the usual range for Balb/c mice. Six mice are now sacrificed and put through an autopsy. Treatment is started twice daily by oral gavage (12 mice per treatment group) with 25 mg/kg Momelotinib sulfate (CYT387 sulfate salt), 50 mg/kg Momelotinib sulfate (CYT387 sulfate salt), or vehicle for the remaining animals. Within 6 days of treatment beginning, both dose cohorts show a sharp reduction in white cell counts, and after 20 days, there is a noticeable decline in hematocrit[2]. Momelotinib sulfate (CYT387 sulfate salt) has an apparent half life of 2.4 hours, a quantitative absolute oral bioavailability, and high plasma concentrations (Cmax= 40.4 μM; Tmax= 4 h) following oral administration. The low blood clearance of momelotinib sulfate (CYT387 sulfate salt) (6.3 mL/min/kg) and consequently poor susceptibility to hepatic first pass metabolism are probably contributing factors to the drug's high oral bioavailability[3].

Absorption, Distribution and Excretion
Mometinib is rapidly absorbed after oral administration, with a bioavailability of 97%. At the maximum recommended dose, the mean (%CV) steady-state Cmax is 479 ng/mL (61%), and the mean (%CV) AUC is 3,288 ng·h/mL (60%). Mometinib exposure (i.e., Cmax and AUC) increases proportionally with dose from 100 mg to 300 mg (0.5 to 1.5 times the maximum recommended dose), but the increase in exposure is less proportional to the dose in the dose range of 400 mg to 800 mg (2 to 4 times the maximum recommended dose). No clinically significant accumulation is observed. Steady-state Tmax is 2 hours after administration (Q1: 1 hour; Q3: 3 hours). In healthy subjects, no clinically significant differences in the pharmacokinetics of mometinib were observed regardless of whether a high-fat meal (800 kcal; 50% fat) or a low-fat meal (400 kcal; 20% fat) was consumed. Mometinib is primarily excreted in feces, with a small amount excreted in urine. Following a single oral administration of radiolabeled mometinib to healthy subjects, approximately 69% of the total radioactive dose was recovered in feces, with M14 accounting for 21.4%, mometinib and M21 each accounting for 13%, and the remaining 22% as 12 other metabolites. Approximately 28% of the radioactive material was recovered in urine, with M21 being the major metabolite. The mean steady-state apparent volume of distribution (%CV) was 984 L (118%). The mean clearance (%CV) was 103 L/h (87%).

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Metabolism/Metabolites Mometinib is metabolized by a variety of cytochrome P450 (CYP) enzymes, including CYP3A4 (36%), CYP2C8 (19%), CYP2C9 (17%), CYP2C19 (19%), and CYP1A2 (9%). M21 is initially generated by the oxidation of the morpholine ring by the above-mentioned CYP enzymes, and subsequently metabolized by aldehyde oxidases. M21 is the major metabolite in the human body, retaining approximately 40% of the pharmacological activity of the parent drug. The average AUC ratio of M21 to momelotinib ranges from 1.4 to 2.1. Momelotinib can undergo amide hydrolysis, N-dealkylation, nitrile hydrolysis, nitrile oxidation, and glucuronidation.

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Biological Half-Life The elimination half-life of momelotinib and its metabolite M21 is 4 to 8 hours.

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Oral bioavailability in rats: Male Sprague-Dawley rats (250–300 g) were administered Momelotinib (LM1149; CYT387; CYT11387) by gavage (10 mg/kg) or intravenous injection (2 mg/kg): - Oral bioavailability = 50%; - Oral administration: Cmax = 3.1 μg/mL (Tmax = 1.6 h), terminal half-life (t1/2) = 4.3 h, AUC0-24h = 17.2 μg·h/mL; - Intravenous administration: Cmax = 7.9 μg/mL, t1/2 = 3.9 h, AUC0-∞ = 34.4 μg·h/mL [1]
- Plasma protein binding rate: In human plasma, the protein binding rate of mometinib (LM1149; CYT387; CYT11387) was 93% (as determined by 37°C equilibrium dialysis method) [1]
- MPN mouse tissue distribution: Two hours after oral administration of mometinib (LM1149; CYT387; CYT11387) (60 mg/kg) to MPN mice, the bone marrow concentration was 4.8 μg/g and the spleen concentration was 4.5 μg/g, which was about 1.5 times the plasma concentration (3.2 μg/mL) [3]

Hepatotoxicity
In published pre-registration clinical trials of mometinib, the incidence of elevated serum ALT or AST levels ranged from 21% to 31%, with 0.5% to 2.0% of patients having ALT or AST levels exceeding the upper limit of normal (ULN) by 5 times, and 0.5% having ALT or AST levels exceeding the ULN by 20 times. In the safety cohort of 448 patients treated with mometinib, two patients experienced clinically significant but spontaneously resolving liver injury with jaundice. Another patient developed liver injury with jaundice, suspected to be caused by hepatitis B virus reactivation. This liver injury was typically hepatocellular, without immune hypersensitivity or autoimmune characteristics, and appeared 2 to 4 months after treatment, resolving rapidly upon discontinuation of the drug. Peak ALT elevations ranged from 308 to 1178 U/L, and peak bilirubin elevations ranged from 2.3 to 7.0 mg/dL. There were no deaths due to liver failure. Since its approval and wider clinical application, no further cases of elevated serum enzymes or bilirubin or clinically significant liver injury have been reported, but the use of this drug is limited.
Probability Score: D (May cause clinically significant liver injury, including hepatitis B virus reactivation).

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Effects during pregnancy and lactation>
◉ Overview of use during lactation
There is currently no information regarding the clinical use of mometinib during lactation. Because mometinib binds to plasma proteins at a rate of 91%, its content in breast milk may be low. The manufacturer recommends discontinuing breastfeeding during mometinib treatment and for at least one week after the last dose.
◉ 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>
In healthy volunteers, mometinib binds to plasma proteins at a rate of 91%.

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Repeated-dose toxicity in rodents: Male/female Sprague-Dawley rats (n=4 per sex per group) were treated with momelotinib (LM1149; CYT387; CYT11387) (5/30/100 mg/kg, orally, once daily) for 28 days: - No deaths; No adverse events observed at the NOAEL of 30 mg/kg; - 100 mg/kg dose group: Mild thrombocytopenia (platelet count decreased by 20% compared to the control group), no histopathological changes in the liver and kidneys; no changes in serum ALT/AST/creatinine levels [1]
- Safety in MPN mice: Momelotinib (LM1149; CYT387; CYT11387) (maximum dose 60 mg/kg, orally, for 28 days) resulted in a weight loss of ≤4%, with no significant toxicity (e.g., somnolence, diarrhea), and normal serum creatinine/BUN levels [3]
- Safety in normal cells in vitro: After treating human peripheral blood mononuclear cells (PBMCs) with Momelotinib (LM1149; CYT387; CYT11387) (≤10 μM) for 72 hours, cell viability was >85% (MTT assay), and no significant apoptosis was observed [1]

[1]. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia, 2009, 23(8), 1441-1445.

[2]. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood, 2010, 115(25), 5232-5240.

[3]. Phenylaminopyrimidines as inhibitors of Janus kinases (JAKs). Bioorg Med Chem Lett. 2009 Oct 15;19(20):5887-92.

C23H22N6O2.2[H2O4S]

610.61674

610.115

1056636-06-6

Momelotinib;1056634-68-4;Momelotinib Mesylate;1056636-07-7 Momelotinib sulfate;1056636-06-6; 1380317-28-1 (HCl)

66576992

Light yellow to yellow solid powder

4.362

6

15

6

41

696

0

CS(=O)(=O)O.C1COCCN1C2=CC=C(C=C2)NC3=NC=CC(=N3)C4=CC=C(C=C4)C(=O)NCC#N

XJGPMRGWDSQVTN-UHFFFAOYSA-N

InChI=1S/C23H22N6O2.2H2O4S/c24-10-12-25-22(30)18-3-1-17(2-4-18)21-9-11-26-23(28-21)27-19-5-7-20(8-6-19)29-13-15-31-16-14-29;2*1-5(2,3)4/h1-9,11H,12-16H2,(H,25,30)(H,26,27,28);2*(H2,1,2,3,4)

N-(cyanomethyl)-4-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]benzamide;sulfuric acid

Ojjaara; momelotinib Mesylate; 1056636-07-7; CYT387 Mesylate; CYT387 (Mesylate); N-(cyanomethyl)-4-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]benzamide;methanesulfonic acid;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO : ~220 mg/mL (~360.29 mM)
H2O : ~100 mg/mL (~163.77 mM)

Solubility in Formulation 1: ≥ 5.5 mg/mL (9.01 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 55.0 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.

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Solubility in Formulation 2: ≥ 5.5 mg/mL (9.01 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 55.0 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.

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Solubility in Formulation 3: ≥ 5.5 mg/mL (9.01 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 55.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (163.77 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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