JAK3- in -11 (Compound 12) 是表现出强效的、无细胞毒性、不可逆、口服活性的JAK3抑制活性，IC50值为1.7 nM，具有出色的选择性(高于其他 JAK3 亚型的588倍)，共价结合到 JAK3 的 ATP-binding pocket。 JAK3-IN-11 强烈抑制 JAK3 依赖的信号转导和T细胞增殖，是研究自身免疫性疾病的有效工具。

JAK3-IN-11 (Compound 12) exhibits potent, noncytotoxic, irreversible, orally active JAK3 inhibitory activity (IC50 = 1.7 nM) with an excellent selectivity profile (>588-fold compared to other JAK isoforms), covalently binds to the ATP-binding pocket in JAK3. JAK3-IN-11 strongly inhibits JAK3-dependent signaling and T-cell proliferation which is a promising tool for studying autoimmune diseases [1].

JAK3-IN-11 (Compound 12) (10 μM, 72 h) has no obvious cytotoxicity at a concentration of 10 μM [1]. JAK3-IN-11 (Compound 12) (72 h) shows strong inhibition for T cell proliferation with IC 50 values of 0.83 μM (anti-CD3/CD28 stimulation) and 0.77 μM (IL-2 stimulation) [1]. JAK3-IN-11 (Compound 12) (0-10 μM, 1h) abrogates IL-2 or IL-15-induced phosphorylation of STAT5 in a concentration-dependent manner [1]. JAK3-IN-11 (Compound 12) covalently binds to JAK3 and irreversibly inhibits JAK3 [1]. Cell Proliferation Assay [1] Cell Line: Mouse T cells in complete RPMI1640 medium then exposed to anti-CD3/anti-CD28 or IL-2. Concentration: Incubation Time: 72 h. Result: Displayed strong inhibition for T cell proliferation with an IC 50 values of 0.83 μM (anti-CD3/CD28 stimulation) and 0.77 μM (IL-2 stimulation), showed obvious significant immunosuppressive activity under selective inhibition of JAK3. Western Blot Analysis [1] Cell Line: Purified T cells were pre-activated coated with anti-CD3 and anti-CD28 for 72 h, then cultured with IL-2 (50 U/mL) for 36 h, then, cultured without IL-2 for 36 h Concentration: 0.01, 0.1, 1, 10 μM. Incubation Time: 1 h. Result: Abrogated IL-2 or IL-15-induced phosphorylation of STAT5 in a concentration-dependent manner.

JAK3-IN-11 (Compound 12) (Oxazolone (OXZ)-induced DTH Balb/c mice; 0-30 mg/kg; PO, prior to and during the challenge phase, 6 days) inhibits oxazolone (OXZ)-induced delayed type hypersensitivity (DTH) responses in a dose-dependent manner [1]. Animal Model: Oxazolone (OXZ)-induced DTH Balb/c mice model [1]. Dosage: 30, 10, and 3 mg/kg. Administration: PO, prior to and during the challenge phase, 6 days. Result: Dose-dependently inhibited oxazolone (OXZ)-induced delayed-type hypersensitivity (DTH) responses. Animal Model: Male ICR mice [1]. Dosage: 30 mg/kg for oral gavage, 10 mg/kg for intravenous administration. Administration: Pharmacokinetic Analysis Result: Preliminary pharmacokinetic data of JAK3-IN-11 (Compound 12) in male ICR Mice [1] Male ICR mice, 30 mg/kg for oral gavage, 10 mg/kg for intravenous administration [1]. Compound 12 iv (10 mg/kg) po (30 mg/kg) AUC(0-t) (mg/L*h) a 1244.41 ± 77.83 889.42 ± 48.32 AUC(0-∞) (mg/L*h) 1274.41 ± 57.18 897.12 ± 56.72 MRT (0-∞) (h) b 0.73 ± 0.08 1.42 ± 0.38 Vz (L/kg) c 8.36 ± 1.83 220.42 ± 24.71 CLz (L/h/kg) d 8.15 ± 1.21 97.14 ± 20.87 t 1/2 (h) e 0.47 ± 0.06 1.52 ± 0.34 C max (mg/L) f 8763.23 ± 324.65 2008.21 ± 189.44 Bioavailability(%) g 23.82% a Area under the concentration time curve. b Mean residence time. c Volume in steady state. d Plasma clearance. e Terminal half-life. f Peak plasma concentrations. g Bioavailability = AUC 0-t (po)/AUC 0-t × 100%.

2412734-00-8

C23H23N5O2

401.46

JAK3-IN-11

(< 1 mg/ml refers to the product slightly soluble or insoluble )
Powder: -20°C for 3 years
In solvent: -80°C for 2 years