当前位置: X-MOL 学术ACS Med. Chem. Lett. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Hydrogen Peroxide Inducible JAK3 Covalent Inhibitor: Prodrug for the Treatment of RA with Enhanced Safety Profile
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-10-05 , DOI: 10.1021/acsmedchemlett.0c00323
Qichao Bao 1, 2 , Liangying Zhang 1, 2 , Nan Wang 3 , Brian Gabet 3 , Weikang Yang 1, 2 , Xingyang Gao 1, 2 , Qidong You 1, 2 , Zhengyu Jiang 1, 2
Affiliation  

Selective inhibition of Janus kinases (JAKs) is an arising strategy in drug discovery. Covalent inhibitors targeting a unique cysteine in JAK3 exhibit ultraselectivity among JAK family members. However, safety and tissue specific concerns still remain. A prodrug of a known JAK3 covalent inhibitor sensitive to H2O2 was designed and synthesized and its therapeutic effect was evaluated in the CIA (collagen-induced arthritis) mice model of RA (rheumatoid arthritis). The prodrug strategy relied on the introduction of a hydrogen peroxide-sensitive borate trigger group to avoid random covalent binding to thiol functionalities in biomacromolecules. The results show that the prodrug can be activated and released under pathophysiological concentration of H2O2. In addition, the prodrug demonstrated stability to the physiological environment. In comparison to the parent compound, the prodrug showed a similar therapeutic effect in the CIA model but notably exhibited lower toxicity and a larger therapeutic window.

中文翻译:

过氧化氢诱导型 JAK3 共价抑制剂:具有增强安全性的治疗 RA 的前药

Janus 激酶 (JAK) 的选择性抑制是药物发现中的一种新兴策略。针对 JAK3 中独特半胱氨酸的共价抑制剂在 JAK 家族成员中表现出超选择性。然而,安全性和组织特异性问题仍然存在。设计并合成了一种已知的对 H 2 O 2敏感的 JAK3 共价抑制剂的前药,并在 RA(类风湿性关节炎)的 CIA(胶原诱导性关节炎)小鼠模型中评估了其治疗效果。前药策略依赖于引入过氧化氢敏感的硼酸盐触发基团,以避免与生物大分子中的硫醇官能团随机共价结合。结果表明,在病理生理浓度的H 2 O下,前药可以被激活和释放。2 . 此外,前药表现出对生理环境的稳定性。与母体化合物相比,前药在 CIA 模型中显示出类似的治疗效果,但显着地表现出较低的毒性和较大的治疗窗口。
更新日期:2020-11-12
down
wechat
bug