Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of ((S)-2,2-Difluorocyclopropyl)((1R,5S)-3-(2-(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841)

被引：133

作者：

Fensome, Andrew ^{[1
]}

Ambler, Catherine M. ^{[2
]}

Arnold, Eric ^{[2
]}

Banker, Mary Ellen ^{[2
]}

Brown, Matthew F. ^{[2
]}

Chrencik, Jill ^{[2
]}

Clark, James D. ^{[3
]}

Dowty, Martin E. ^{[1
]}

Efremov, Ivan V. ^{[1
]}

Flick, Andrew ^{[2
]}

Gerstenberger, Brian S. ^{[1
]}

Gopalsamy, Ariamala ^{[1
]}

Hayward, Matthew M. ^{[2
]}

Hegen, Martin ^{[3
]}

Hollingshead, Brett D. ^{[4
]}

Jussif, Jason ^{[3
]}

Knafels, John D. ^{[2
]}

Limburg, David C. ^{[2
]}

Lin, David ^{[2
]}

Lin, Tsung H. ^{[3
]}

Pierce, Betsy S. ^{[2
]}

Saiah, Eddine ^{[1
]}

Sharma, Raman ^{[2
]}

Symanowicz, Peter T. ^{[3
]}

Telliez, Jean-Baptiste ^{[3
]}

Trujillo, John I. ^{[2
]}

Vajdos, Felix F. ^{[2
]}

Vincent, Fabien ^{[2
]}

Wan, Zhao-Kui ^{[1
]}

Xing, Li ^{[1
]}

Yang, Xiaojing ^{[1
]}

Yang, Xin ^{[2
]}

Zhang, Liying ^{[1
]}

机构：

[1] Pfizer Inc, Med Design, 1 Portland St, Cambridge, MA 02139 USA

[2] Pfizer Inc, Med Design, Eastern Point Rd, Groton, CT 06340 USA

[3] Pfizer Inc, Inflammat & Immunol, 1 Portland St, Cambridge, MA 02139 USA

[4] Pfizer Inc, Drug Safety Res & Dev, 1 Portland St, Cambridge, MA 02139 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 19期

关键词：

JANUS KINASE INHIBITOR; RHEUMATOID-ARTHRITIS; PRECLINICAL CHARACTERIZATION; INFLAMMATORY DISEASES; INADEQUATE RESPONSE; EFFICACY; SAFETY; TOFACITINIB; MODELS; PHARMACOKINETICS;

D O I：

10.1021/acs.jmedchem.8b00917

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 gamma-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).

引用

页码：8597 / 8612

页数：16

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