2. Academic Validation
  3. 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)

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)

  • J Med Chem. 2018 Oct 11;61(19):8597-8612. 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
Affiliations

Affiliations

  • 1 Medicine Design, Pfizer Inc., 1 Portland Street , Cambridge , Massachusetts 02139 , United States.
  • 2 Medicine Design, Pfizer Inc., Eastern Point Road , Groton , Connecticut 06340 , United States.
  • 3 Inflammation and Immunology, Pfizer Inc., 1 Portland Street , Cambridge , Massachusetts 02139 , United States.
  • 4 Drug Safety Research and Development, Pfizer Inc., 1 Portland Street , Cambridge , Massachusetts 02139 , United States.
PMID: 30113844 DOI: 10.1021/acs.jmedchem.8b00917
Abstract

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).

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