Momelotinib Chemical Properties

Density 

1.292

storage temp. 

Store at -20°C

solubility 

insoluble in EtOH; insoluble in H2O; ≥20.7 mg/mL in DMSO

pka

10.94±0.46(Predicted)

form 

Orange powder.

color 

Light yellow to yellow

InChI

InChI=1S/C23H22N6O2/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/h1-9,11H,12-16H2,(H,25,30)(H,26,27,28)

InChIKey

ZVHNDZWQTBEVRY-UHFFFAOYSA-N

SMILES

C(NCC#N)(=O)C1=CC=C(C2C=CN=C(NC3=CC=C(N4CCOCC4)C=C3)N=2)C=C1

CAS DataBase Reference

1056634-68-4

Momelotinib Usage And Synthesis

Description

Momelotinib (CYT387) is an ATP-competitive inhibitor of JAK1/JAK2 with IC50 of 11 nM/18 nM, ~10-fold selectivity versus JAK3. Phase 3.

In vitro

CYT387 inhibits the proliferation of parental Ba/F3 cells (Ba/F3-wt) stimulated by IL-3 with IC50 of 1400 nM. Furthermore, CYT387 also causes the inhibition of cell proliferation in cell lines constitutively activated by JAK2 or MPL signaling, including Ba/F3-MPLW515L cells, CHRF-288-11 cells and Ba/F3-TEL-JAK2 cells with IC50 of 200 nM, 1 nM and 700 nM, respectively. In addition, CYT387 has been shown to inhibit erythroid colony growth in vitro from JAK2V617F-positive PV patients with similar potency with IC50 of 2μ-4 μM. A recent study shows that CYT387 inhibits PI3K/AKT and Ras/MAPK signaling induced by IL-6 and IGF-1. Moreover, CYT387 induces apoptosis as a single agent and synergizes with the conventional anti-MM therapies bortezomib and melphalan in primary multiple myeloma (MM) cells.

In vivo

In a murine MPN model, CYT387 normalizes white cell counts, hematocrit, spleen size, and restores physiologic levels of inflammatory cytokines.

Uses

CYT387 inhibits Janus kinase 1 (JAK1) and Janus kinase (JAK2). These kinases are part of the JAK-STAT pathway and dysregulated functions are involved with hematology, oncology and inflammatory diseases.

Definition

ChEBI: Momelotinib is a benzamide obtained by formal condensation of the carboxy group of 4-{2-[4-(morpholin-4-yl)anilino]pyrimidin-4-yl}benzoic acid with the primary amino group of aminoacetonitrile. It is an ATP-competitive JAK1/JAK2 inhibitor with IC50 of 11 nM and 18 nM, respectively. Used for the treatment of patients with intermediate- or high-risk myelofibrosis. It has a role as an EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor, an antineoplastic agent, an anti-anaemic agent and an apoptosis inducer. It is an aminopyrimidine, a member of morpholines, a secondary amino compound, a tertiary amino compound, a member of benzamides and a nitrile.

Biological Activity

cyt387, an aminopyrimidine derivative discovered by high-throughput enzyme and cell-based screening along with the optimization using structure-guided medicinal chemistry, is a potent and selective inhibitor of janus kinase 1 (jak1), janus kinase 2 (jak2) and tyrosine kinase 2 (tyk2) with values of 50% inhibition concentration ic50 of 11 nm, 18 nm, 155 nm and 17 nm respectively. recent studies have revealed that cyt387, at low nanomolar concentrations ranging between 500 and 1500 nm, is able to inhibit jak2 signaling pathway, suppress proliferation and induce apoptosis in jak2-dependent hematopoietic cell lines with non-hematopoietic cell lines intact.tyner jw, bumm tg, deininger j, wood l, aichberger kj, loriaux mm, druker bj, burns cj, fantino e, deininger mw. cyt387, a novel jak2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. blood. 2010;115(25):5232-5240.

Synthesis

Triethylamine (Et3N, 4.1 mL, 30 mmol) was added to a solution of N,N-dimethylformamide (DMF, 20 mL) containing 4-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)benzoic acid (1.88 g, 5.0 mmol). Aminoacetonitrile hydrochloride (0.93 g, 10 mmol), N-hydroxybenzotriazole (HOBt, 0.81 g, 6.0 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 1.1 g, 6.0 mmol) were then added sequentially. The reaction mixture was stirred at room temperature overnight. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure and the residue was dissolved in dichloromethane (CH2Cl2, 100 mL) and washed with saturated aqueous sodium bicarbonate (NaHCO3). The organic phase was dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) with ethyl acetate (EtOAc) as eluent to afford N-(cyanomethyl)-4-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)benzamide (Momotinib) as a yellow solid with a yield of 1.86 g (90% yield) and a melting point of 232- 234°C (literature value 238-243°C IR (cm-1): 3365, 3282, 1660, 1596, 1576, 1512, 1456, 1232. elemental analysis (C23H22N6O2) calculated: C, 66.65; H, 5.35; N, 20.28; measured: C, 66.78; H, 5.49; N, 20.39. ESI-MS: m/z 415.1 [M + M + N]. z 415.1 [M + H]+, 437.1 [M + Na]+, 413.2 [M - H]-. 1H NMR (300 MHz, DMSO-d6): δ 9.47 (s, 1H), 9.32 (t, J = 5.4 Hz, 1H), 8.54 (d, J = 5.1 Hz, 1H), 8.27 (d, J = 8.1 Hz, 2H), 8.03 (d, J = 8.1 Hz, 2H), 8.03 (d, J = 8.1 Hz, 2H). 8.03 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 5.1 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 4.35 (d, J = 5.1 Hz, 2H), 3.74-3.77 (m, 4H), 3.04-3.07 (m, 4H).13C NMR (75 MHz, DMSO-d6): δ 166.1, 162.4, 160.3, 159.2, 146.2, 139.9, 134.5, 132.8, 127.8, 126.9, 120.3, 117.5, 115.6, 107.6, 66.1, 49.2, 27.7.

in vivo

target

JAK1

IC 50

JAK1: 11 nM (IC₅₀); JAK2: 18 nM (IC₅₀); JAK3: 155 nM (IC₅₀)

References

[1] Journal of Chemical Research, 2016, vol. 40, # 8, p. 511 - 513
[2] Patent: , 2016, . Location in patent: Paragraph 0049; 0050; 0051; 0052; 0053; 0054
[3] Patent: WO2008/109943, 2008, A1. Location in patent: Page/Page column 58
[4] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2902 - 2905
[5] Patent: EP2949647, 2015, A1. Location in patent: Paragraph 0124

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