Liang Jun, Van Abbema Anne, Balazs Mercedesz, Barrett Kathy, Berezhkovsky Leo, Blair Wade S, Chang Christine, Delarosa Donnie, DeVoss Jason, Driscoll Jim, Eigenbrot Charles, Goodacre Simon, Ghilardi Nico, MacLeod Calum, Johnson Adam, Bir Kohli Pawan, Lai Yingjie, Lin Zhonghua, Mantik Priscilla, Menghrajani Kapil, Nguyen Hieu, Peng Ivan, Sambrone Amy, Shia Steven, Smith Jan, Sohn Sue, Tsui Vickie, Ultsch Mark, Williams Karen, Wu Lawren C, Yang Wenqian, Zhang Birong, Magnuson Steven
Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Bioorg Med Chem Lett. 2017 Sep 15;27(18):4370-4376. doi: 10.1016/j.bmcl.2017.08.022. Epub 2017 Aug 12.
Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients.
在此，我们报告通过对连接化合物1吡啶环和芳基环的可旋转酰胺键进行限制，鉴定出一类咪唑并吡啶类强效且选择性的TYK2抑制剂，以原型6为例。进一步优化得到了化合物30，其能有效抑制细胞中的TYK2酶和IL-23通路，对细胞JAK2活性具有选择性，并且具有良好的药代动力学性质。在小鼠中，化合物30在药代动力学/药效学（PK/PD）模型以及咪喹莫特诱导的银屑病模型中均显示出剂量依赖性的IL-17产生减少。在该疗效模型中，IL-17的降低伴随着耳部厚度的减小，表明抑制TYK2作为银屑病患者的一种治疗方法具有潜力。
