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Identification of Imidazo[1,2-b]pyridazine Derivatives as Potent, Selective, and Orally Active Tyk2 JH2 Inhibitors

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    Identification of Imidazo[1,2-b]pyridazine Derivatives as Potent, Selective, and Orally Active Tyk2 JH2 Inhibitors
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    • Chunjian Liu*
      Chunjian Liu
      Research & Development, Bristol-Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543, United States
      *Tel: +1 609 466 5101. E-mail: [email protected]
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      Orcidhttp://orcid.org/0000-0003-3708-2372
    • James Lin
      James Lin
      Research & Development, Bristol-Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543, United States
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    • Ryan Moslin
      Ryan Moslin
      Research & Development, Bristol-Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543, United States
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      John S. Tokarski
      Research & Development, Bristol-Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543, United States
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    • Jodi Muckelbauer
      Jodi Muckelbauer
      Research & Development, Bristol-Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543, United States
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      ChiehYing Chang
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      Jeffrey Tredup
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      Dianlin Xie
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      Hyunsoo Park
      Research & Development, Bristol-Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543, United States
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    • Peng Li
      Peng Li
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      Dauh-Rurng Wu
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      Lihong Cheng
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      Charu Chaudhry
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      Cliff Chen
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      Kathleen Gillooly
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      Luisa Salter-Cid
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      Louis J. Lombardo
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      Nelly Aranibar
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      James R. Burke
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      David S. Weinstein
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    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2019, 10, 3, 383–388
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    https://doi.org/10.1021/acsmedchemlett.9b00035
    Published February 21, 2019
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    Abstract

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    In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-N1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-b]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure–activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor 6, which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.

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    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2019, 10, 3, 383–388
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsmedchemlett.9b00035
    Published February 21, 2019
    Copyright © 2019 American Chemical Society
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