当前位置：
X-MOL 学术
›
J. Med. Chem.
›
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.)
Discovery of Tyrosine Kinase 2 (TYK2) Inhibitor (PF-06826647) for the Treatment of Autoimmune Diseases.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-08-05 , DOI: 10.1021/acs.jmedchem.0c00948
Brian S Gerstenberger 1 , Catherine Ambler 2 , Eric P Arnold 2 , Mary-Ellen Banker 2 , Matthew F Brown 2 , James D Clark 1 , Alpay Dermenci 2 , Martin E Dowty 1 , Andrew Fensome 1 , Susan Fish 1 , Matthew M Hayward 2 , Martin Hegen 1 , Brett D Hollingshead 1 , John D Knafels 2 , David W Lin 2 , Tsung H Lin 1 , Dafydd R Owen 1 , Eddine Saiah 1 , Raman Sharma 2 , Felix F Vajdos 2 , Li Xing 1 , Xiaojing Yang 2 , Xin Yang 2 , Stephen W Wright 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-08-05 , DOI: 10.1021/acs.jmedchem.0c00948
Brian S Gerstenberger 1 , Catherine Ambler 2 , Eric P Arnold 2 , Mary-Ellen Banker 2 , Matthew F Brown 2 , James D Clark 1 , Alpay Dermenci 2 , Martin E Dowty 1 , Andrew Fensome 1 , Susan Fish 1 , Matthew M Hayward 2 , Martin Hegen 1 , Brett D Hollingshead 1 , John D Knafels 2 , David W Lin 2 , Tsung H Lin 1 , Dafydd R Owen 1 , Eddine Saiah 1 , Raman Sharma 2 , Felix F Vajdos 2 , Li Xing 1 , Xiaojing Yang 2 , Xin Yang 2 , Stephen W Wright 2
Affiliation
|
Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family that regulates signal transduction downstream of receptors for the IL-23/IL-12 pathways and type I interferon family, where it pairs with JAK2 or JAK1, respectively. On the basis of human genetic and emerging clinical data, a selective TYK2 inhibitor provides an opportunity to treat autoimmune diseases delivering a potentially differentiated clinical profile compared to currently approved JAK inhibitors. The discovery of an ATP-competitive pyrazolopyrazinyl series of TYK2 inhibitors was accomplished through computational and structurally enabled design starting from a known kinase hinge binding motif. With understanding of PK/PD relationships, a target profile balancing TYK2 potency and selectivity over off-target JAK2 was established. Lead optimization involved modulating potency, selectivity, and ADME properties which led to the identification of the clinical candidate PF-06826647 (22).
中文翻译：
发现用于治疗自身免疫性疾病的酪氨酸激酶2（TYK2）抑制剂（PF-06826647）。
酪氨酸激酶2（TYK2）是JAK激酶家族的成员，该家族调节IL-23 / IL-12途径和I型干扰素家族的受体下游的信号传导，并分别与JAK2或JAK1配对。根据人类遗传学和新兴的临床数据，与目前批准的JAK抑制剂相比，选择性TYK2抑制剂为治疗自身免疫性疾病提供了机会，可提供具有潜在差异性的临床特征。ATP竞争性吡唑并吡嗪基系列TYK2抑制剂的发现是通过从已知的激酶铰链结合基序开始的计算和结构上可行的设计完成的。了解了PK / PD关系后，建立了一个目标配置文件，该目标配置文件平衡了TYK2的效能和相对于脱靶JAK2的选择性。潜在客户优化涉及调节效能，22）。
更新日期：2020-08-05
中文翻译：
发现用于治疗自身免疫性疾病的酪氨酸激酶2（TYK2）抑制剂（PF-06826647）。
酪氨酸激酶2（TYK2）是JAK激酶家族的成员，该家族调节IL-23 / IL-12途径和I型干扰素家族的受体下游的信号传导，并分别与JAK2或JAK1配对。根据人类遗传学和新兴的临床数据，与目前批准的JAK抑制剂相比，选择性TYK2抑制剂为治疗自身免疫性疾病提供了机会，可提供具有潜在差异性的临床特征。ATP竞争性吡唑并吡嗪基系列TYK2抑制剂的发现是通过从已知的激酶铰链结合基序开始的计算和结构上可行的设计完成的。了解了PK / PD关系后，建立了一个目标配置文件，该目标配置文件平衡了TYK2的效能和相对于脱靶JAK2的选择性。潜在客户优化涉及调节效能，22）。
京公网安备 11010802027423号