Tyk2-IN-5 (compound 6) 是一种强效的、具有选择性和口服活性的酪氨酸激酶 2 (Tyk2) 抑制剂，作用于JH2结构域。Tyk2-IN-5 对Tyk2 JH2的Ki值为 0.086 nM，对 IFNα 的IC50值为 25 nM。Tyk2-IN-5 能高效地抑制药效学大鼠模型中 IFNγ 的产生，对大鼠关节炎模型具有完全的疗效。
| 生物活性 | Tyk2-IN-5 (compound 6) is a potent, selective and orally activetyrosine kinase 2(Tyk2) inhibitor that acts on theJH2structural domain. Tyk2-IN-5 shows aKivalue of 0.086 nM forTyk2JH2and anIC50value of 25 nM for IFNα. Tyk2-IN-5 efficiently inhibits the production of IFNγ in a pharmacodynamic rat model and is fully efficacious in a rat model of arthritis[1]. |
| IC50& Target[1] | Tyk2 JH2 0.086 nM (Ki) | IFNα 25 nM (IC50) |
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体外研究
(In Vitro) | Tyk2-IN-5 inhibits Jak1-3 with IC50values of >2 μM and displays the Jak1-3 dependent cellular activities of >12.5 μM (IC50values)[1].
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体内研究
(In Vivo) | Tyk2-IN-5 (5, 10 mg/kg; p.o.; twice daily for 20 days) shows highly efficacious in a rat adjuvant arthritis model[1].
Tyk2-IN-5 (1, 10 mg/kg; p.o.; single) inhibits IL-12/IL-18 induced IFNγ production in a dose-dependent manner[1].
Tyk2-IN-5 (10 mg/kg; p.o.; single) shows a high oral exposure and bioavailability (114%) in rat[1].
| Animal Model: | Lewis male rats (rat adjuvant arthritis model)[1]. | | Dosage: | 5, 10 mg/kg | | Administration: | Oral administration; twice daily for 20 days | | Result: | Demonstrated full efficacy to prevent the rats′ paw from swelling. |
| Animal Model: | Lewis male rats (IL-12/IL-18-induced)[1]. | | Dosage: | 1, 10 mg/kg | | Administration: | Oral administration; single | | Result: | Inhibited IL-12/IL-18 induced IFNγ production by 45% and 77% at doses of 1 and 10 mg/kg, respectively. |
| Animal Model: | Lewis male rats, mouse[1]. | | Dosage: | 10 mg/kg | | Administration: | Oral administration; single | | Result: | 1.19Pharmacokinetic Parameters of Tyk2-IN-5 in mouse and rat[1].
| PO (10 mg/kg) | | mouse | rat | | Cmax(μM) | 15 | 9.4 | | AUC0-24(μMoh) | 19 | 57 | | CL (mL/min/kg) | 16 | 7.8 | | F (%) | 86 | 114 |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | | Powder | -20°C | 3 years | | 4°C | 2 years | | In solvent | -80°C | 6 months | | -20°C | 1 month |
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| 溶解性数据 | In Vitro: DMSO : 43.33 mg/mL(99.74 mM;Need ultrasonic) 配制储备液 | 1 mM | 2.3019 mL | 11.5093 mL | 23.0187 mL | | 5 mM | 0.4604 mL | 2.3019 mL | 4.6037 mL | | 10 mM | 0.2302 mL | 1.1509 mL | 2.3019 mL |
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