Medicine Design, Pfizer Inc., 1 Portland Street , Cambridge , Massachusetts 02139 , United States.
Medicine Design, Pfizer Inc., Eastern Point Road , Groton , Connecticut 06340 , United States.
J Med Chem. 2018 Oct 11;61(19):8597-8612. doi: 10.1021/acs.jmedchem.8b00917. Epub 2018 Aug 16.
Cytokine signaling is an important characteristic of autoimmune diseases. Many pro-inflammatory cytokines signal through the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) pathway. JAK1 is important for the γ-common chain cytokines, interleukin (IL)-6, and type-I interferon (IFN) family, while TYK2 in addition to type-I IFN signaling also plays a role in IL-23 and IL-12 signaling. Intervention with monoclonal antibodies (mAbs) or JAK1 inhibitors has demonstrated efficacy in Phase III psoriasis, psoriatic arthritis, inflammatory bowel disease, and rheumatoid arthritis studies, leading to multiple drug approvals. We hypothesized that a dual JAK1/TYK2 inhibitor will provide additional efficacy, while managing risk by optimizing selectivity against JAK2 driven hematopoietic changes. Our program began with a conformationally constrained piperazinyl-pyrimidine Type 1 ATP site inhibitor, subsequent work led to the discovery of PF-06700841 (compound 23), which is in Phase II clinical development (NCT02969018, NCT02958865, NCT03395184, and NCT02974868).
细胞因子信号转导是自身免疫性疾病的一个重要特征。许多促炎细胞因子通过 Janus 激酶 (JAK)/信号转导和转录激活因子 (STAT) 途径信号转导。JAK1 对 γ 共链细胞因子、白细胞介素 (IL)-6 和 I 型干扰素 (IFN) 家族很重要，而 TYK2 除了 I 型 IFN 信号转导外，还在 IL-23 和 IL-12 信号转导中发挥作用。用单克隆抗体 (mAb) 或 JAK1 抑制剂进行干预已在 III 期银屑病、银屑病关节炎、炎症性肠病和类风湿关节炎研究中证明具有疗效，导致多种药物获得批准。我们假设双重 JAK1/TYK2 抑制剂将提供额外的疗效，同时通过优化对 JAK2 驱动的造血变化的选择性来管理风险。我们的计划从一个构象受限的哌嗪基嘧啶 1 型 ATP 位点抑制剂开始，随后的工作导致发现了 PF-06700841（化合物 23），它正在进行 II 期临床开发（NCT02969018、NCT02958865、NCT03395184 和 NCT02974868）。
