一种JAK1/3抑制剂的发现以及利用前药在类风湿性关节炎模型中证明疗效
Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of Rheumatoid Arthritis.
作者信息
Spergel Steven H, Mertzman Michael E, Kempson James, Guo Junqing, Stachura Sylwia, Haque Lauren, Lippy Jonathan S, Zhang Rosemary F, Galella Michael, Pitt Sidney, Shen Guoxiang, Fura Aberra, Gillooly Kathleen, McIntyre Kim W, Tang Vicky, Tokarski John, Sack John S, Khan Javed, Carter Percy H, Barrish Joel C, Nadler Steven G, Salter-Cid Luisa M, Schieven Gary L, Wrobleski Stephen T, Pitts William J
机构信息
Research and Development, Bristol-Myers Squibb Company, Route 206 and Provinceline Road, Princeton, New Jersey 08543-4000, United States.
出版信息
ACS Med Chem Lett. 2019 Feb 13;10(3):306-311. doi: 10.1021/acsmedchemlett.8b00508. eCollection 2019 Mar 14.
The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib , has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA.
非受体酪氨酸激酶的Janus家族的四个成员在免疫功能中发挥着重要作用。Janus家族激酶抑制剂托法替布已在美国获批用于类风湿性关节炎（RA）患者。目前，多种具有不同Janus家族选择性谱的Janus激酶抑制剂正处于临床试验阶段。我们的目标是鉴定对JAK1和JAK3具有功能选择性的抑制剂。化合物制备出了所需的功能选择性谱，但因其物理性质导致吸收较差。使用磷酸前药使得能够推进到小鼠胶原诱导性关节炎（CIA）模型。在CIA模型中显示出强大的疗效表明，使用磷酸前药可能解决将这种化学类型推进用于治疗如RA等自身免疫性疾病的问题。
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