Sofnobrutinib (AS-0871) 是口服有效、选择性的BTK抑制剂，抑制激活和未激活 BTK 的IC50分别为 4.2 nM 和 0.39 nM。Sofnobrutinib 也抑制hERG，IC50为 24 μM。Sofnobrutinib 具有良好的代谢稳定性和生物利用度。Sofnobrutinib 的被动皮肤过敏反应低，在胶原诱导的小鼠关节炎模型中具有抗炎作用。
| 生物活性 | Sofnobrutinib (AS-0871) is an orally active and selectiveBTKinhibitor, withIC50s of 4.2 nM (activatedBTK) and 0.39 nM (unactivatedBTK), respectively. Sofnobrutinib also inhibitshERGwith anIC50value of 24 μM. Sofnobrutinib has good metabolic stability and bioavailability. Sofnobrutinib results poor passive cutaneous anaphylaxis reaction, as well as exerting anti-inflammatory effects in collagen-induced arthritis model in mice[1][2]. |
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体外研究
(In Vitro) | Sofnobrutinib (compound 4b) (0.3 μM) 具有优异的激酶选择性，只有两种 Tec 家族激酶 (BMX，TEC) 被抑制。抑制率分别为 80% 和 99.5%[1]。
Sofnobrutinib 显著抑制抗 IgM 诱导的人 PBMC B 细胞活化 (CD86 表达)，IC50值为 13 nM[1]。
Sofnobrutinib (0.0003-1 μM;1 h) 有效抑制 Ramos 细胞中 BTK 和 PLCγ2 的磷酸化[1]。
Western Blot Analysis[1] | Cell Line: | Ramos cells | | Concentration: | 0.0003 μM, 0.001 μM, 0.003 μM, 0.01 μM, 0.03 μM, 0.1 μM, 0.3 μM, 1 μM | | Incubation Time: | 1 hour | | Result: | Inhibited the phosphorylations of BTK (Tyr223, Tyr551) and PLCγ2 (Tyr1217) with IC50s of 19, 14 and 26 nM, respectively. |
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体内研究
(In Vivo) | Sofnobrutinib (10 mg/kg; 口服; 单剂量) 具有良好的生物利用度，在小鼠、大鼠和狗中分别为 65%，44%，和 43%[1]。
Sofnobrutinib (30 mg/kg; 口服; 单剂量) 对被动皮肤过敏 (PCA) 小鼠模型有抑制作用，抑制率为69%[1]。
Sofnobrutinib (15 mg/kg, 30 mg/kg, 60 mg/kg; 口服; 每天两次, 共 19 天) 在胶原诱导的关节炎 (CIA) 小鼠模型中，以剂量依赖的方式抑制关节炎的发展[1]。
药代动力学分析[1]
| Animal | Route | Dose (mg/kg) | t1/2(h) | Tmax(h) | Cmax(ng/mL) | AUC(0-t)(ng·h/mL) | AUC(0-∞)(ng·h/mL) | Vd(L/kg) | Cl (L·h/kg) | MRT0-∞(h) | F (%) | | Mice | iv | 2 | 3.27 | / | 2887 | 3107 | 3114 | 3.03 | 0.64 | 1.30 | / | | po | 10 | 0.95 | 0.50 | 4619 | 10208 | 10242 | / | / | 1.56 | 65.8 | | Rats | iv | 1 | 1.51 | / | 1376 | 1917 | 1960 | 1.10 | 0.51 | 1.79 | / | | po | 10 | 2.44 | 2.00 | 1476 | 8696 | 8706 | / | / | 4.88 | 44.4 | | Dogs | iv | 1 | 3.91 | / | 4963 | 11321 | 11479 | 0.29 | 0.088 | 3.31 | / | | po | 10 | 3.59 | 2.00 | 2090 | 9851 | 10032 | / | / | / | 43.7 |
| Animal Model: | Collagen-induced arthritis (CIA) model in mouse[1] | | Dosage: | 15 mg/kg, 30 mg/kg, 60 mg/kg | | Administration: | Oral gavage; twice daily for 19 days | | Result: | Significantly reduced paw swelling and joint inflammation in a dose-dependent manner. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | Please store the product under the recommended conditions in the Certificate of Analysis. |
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