Islam Imadul, Yuan Shendong, West Christopher W, Adler Marc, Bothe Ulrich, Bryant Judi, Chang Zheng, Chu Kieu, Emayan Kumar, Gualtieri Giovanna, Ho Elena, Light David, Mallari Cornell, Morser John, Phillips Gary, Schaefer Caralee, Sukovich Drew, Whitlow Marc, Chen Deborah, Buckman Brad O
Medical Core Facility and Research Platforms, King Abdullah International Medical Research Center/King Saud Bin, Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh 11426, Saudi Arabia; Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States.
Bioorg Med Chem Lett. 2018 Nov 1;28(20):3372-3375. doi: 10.1016/j.bmcl.2018.09.001. Epub 2018 Sep 5.
We report here the design and synthesis of a novel series of benzylamines that are potent and selective inhibitors of uPA with promising oral availability in rat. Further evaluation of one representative (ZK824859) of the new structural class showed that this compound lowered clinical scores when dosed in either acute or chronic mouse EAE models, suggesting that uPA inhibitors of this type could be useful for the treatment of multiple sclerosis.
我们在此报告了一系列新型苄胺的设计与合成，这些苄胺是强效且选择性的尿激酶型纤溶酶原激活剂（uPA）抑制剂，在大鼠体内具有良好的口服生物利用度。对这一新结构类型的一个代表性化合物（ZK824859）的进一步评估表明，该化合物在急性或慢性小鼠实验性自身免疫性脑脊髓炎（EAE）模型中给药时可降低临床评分，这表明此类uPA抑制剂可能对治疗多发性硬化症有用。
