1056634-68-4

Using ATP kinase assays, the IC50 values for CYT387 are a follows - JAK1 (11nM), JAK2, (18nM), JAK2 V617F (23nM) JAK3 (155nM), and TYK2 (17nM). In testing kinase arrays, CYT387 also had activity (defined as an IC50 < 100nM) detected against CDK2/cyclin A, MAPK8 (JNK1), PRKCN (PKD3), PRKD1 (PKCμ), ROCK2, and TBK1 kinase as well.

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.

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.

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.

JAK1

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

Store at -20°C

[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