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Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of (( S)-2,2-Difluorocyclopropyl)((1 R,5 S)-3-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841).
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-08-16 , DOI: 10.1021/acs.jmedchem.8b00917 Andrew Fensome 1 , Catherine M Ambler 2 , Eric Arnold 2 , Mary Ellen Banker 2 , Matthew F Brown 2 , Jill Chrencik 2 , James D Clark 3 , Martin E Dowty 1 , Ivan V Efremov 1 , Andrew Flick 2 , Brian S Gerstenberger 1 , Ariamala Gopalsamy 1 , Matthew M Hayward 2 , Martin Hegen 3 , Brett D Hollingshead 4 , Jason Jussif 3 , John D Knafels 2 , David C Limburg 2 , David Lin 2 , Tsung H Lin 3 , Betsy S Pierce 2 , Eddine Saiah 1 , Raman Sharma 2 , Peter T Symanowicz 3 , Jean-Baptiste Telliez 3 , John I Trujillo 2 , Felix F Vajdos 2 , Fabien Vincent 2 , Zhao-Kui Wan 1 , Li Xing 1 , Xiaojing Yang 1 , Xin Yang 2 , Liying Zhang 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-08-16 , DOI: 10.1021/acs.jmedchem.8b00917 Andrew Fensome 1 , Catherine M Ambler 2 , Eric Arnold 2 , Mary Ellen Banker 2 , Matthew F Brown 2 , Jill Chrencik 2 , James D Clark 3 , Martin E Dowty 1 , Ivan V Efremov 1 , Andrew Flick 2 , Brian S Gerstenberger 1 , Ariamala Gopalsamy 1 , Matthew M Hayward 2 , Martin Hegen 3 , Brett D Hollingshead 4 , Jason Jussif 3 , John D Knafels 2 , David C Limburg 2 , David Lin 2 , Tsung H Lin 3 , Betsy S Pierce 2 , Eddine Saiah 1 , Raman Sharma 2 , Peter T Symanowicz 3 , Jean-Baptiste Telliez 3 , John I Trujillo 2 , Felix F Vajdos 2 , Fabien Vincent 2 , Zhao-Kui Wan 1 , Li Xing 1 , Xiaojing Yang 1 , Xin Yang 2 , Liying Zhang 1
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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).
中文翻译：
TYK2和JAK1双重抑制治疗自身免疫性疾病：（（S）-2,2-二氟环丙基）（（1 R，5 S）-3-（2-（（1-甲基-1 H-吡唑） -4-基）氨基）嘧啶-4-基）-3,8-二氮杂双环[3.2.1]辛-8-基）甲酮（PF-06700841）。
细胞因子信号传导是自身免疫性疾病的重要特征。许多促炎性细胞因子通过Janus激酶（JAK）/信号转导子和转录激活子（STAT）途径发出信号。JAK1对于γ共有链细胞因子，白介素（IL）-6和I型干扰素（IFN）家族很重要，而TYK2除I型IFN信号传导外在IL-23和IL-12中也起作用信号。单克隆抗体（mAbs）或JAK1抑制剂的干预已在III期银屑病，银屑病关节炎，炎性肠病和类风湿关节炎研究中证明有效，并获得了多种药物的批准。我们假设双重JAK1 / TYK2抑制剂将提供额外的功效，同时通过优化针对JAK2驱动的造血变化的选择性来管理风险。
更新日期：2018-08-16
中文翻译：
TYK2和JAK1双重抑制治疗自身免疫性疾病：（（S）-2,2-二氟环丙基）（（1 R，5 S）-3-（2-（（1-甲基-1 H-吡唑） -4-基）氨基）嘧啶-4-基）-3,8-二氮杂双环[3.2.1]辛-8-基）甲酮（PF-06700841）。
细胞因子信号传导是自身免疫性疾病的重要特征。许多促炎性细胞因子通过Janus激酶（JAK）/信号转导子和转录激活子（STAT）途径发出信号。JAK1对于γ共有链细胞因子，白介素（IL）-6和I型干扰素（IFN）家族很重要，而TYK2除I型IFN信号传导外在IL-23和IL-12中也起作用信号。单克隆抗体（mAbs）或JAK1抑制剂的干预已在III期银屑病，银屑病关节炎，炎性肠病和类风湿关节炎研究中证明有效，并获得了多种药物的批准。我们假设双重JAK1 / TYK2抑制剂将提供额外的功效，同时通过优化针对JAK2驱动的造血变化的选择性来管理风险。
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