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Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Med. Chem. Lett. 2023, 14, 2, 191-198
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    Macrocyclic Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonists
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    • Mark E. Schnute*
      Mark E. Schnute
      Medicine Design, Pfizer Inc., Cambridge, Massachusetts 02139, United States
      *E-mail: [email protected]
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      Orcidhttps://orcid.org/0000-0003-3075-4578
    • John I. Trujillo*
      John I. Trujillo
      Medicine Design, Pfizer Inc., Groton, Connecticut 06340, United States
      *E-mail: [email protected]
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      Orcidhttps://orcid.org/0000-0003-2303-0256
    • Katherine L. Lee
      Katherine L. Lee
      Medicine Design, Pfizer Inc., Cambridge, Massachusetts 02139, United States
      More by Katherine L. Lee
      Orcidhttps://orcid.org/0000-0003-0155-290X
    • Ray Unwalla
      Ray Unwalla
      Medicine Design, Pfizer Inc., Cambridge, Massachusetts 02139, United States
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    • Felix F. Vajdos
      Felix F. Vajdos
      Medicine Design, Pfizer Inc., Groton, Connecticut 06340, United States
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    • Björn Kauppi
      Björn Kauppi
      Karo Pharma AB, 111 48 Stockholm, Sweden
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      Orcidhttps://orcid.org/0000-0002-2813-5180
    • Philippe Nuhant
      Philippe Nuhant
      Medicine Design, Pfizer Inc., Groton, Connecticut 06340, United States
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    • Andrew C. Flick
      Andrew C. Flick
      Medicine Design, Pfizer Inc., Groton, Connecticut 06340, United States
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    • Kimberly K. Crouse
      Kimberly K. Crouse
      Inflammation and Immunology Research, Pfizer Inc., Cambridge, Massachusetts 02139, United States
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    • Yajuan Zhao
      Yajuan Zhao
      Inflammation and Immunology Research, Pfizer Inc., Cambridge, Massachusetts 02139, United States
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    • Amanda Samuel
      Amanda Samuel
      Drug Product Design, Pfizer Inc., San Diego, California 92121, United States
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    • Vincent Lombardo
      Vincent Lombardo
      Medicine Design, Pfizer Inc., Groton, Connecticut 06340, United States
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    • Alexandria P. Taylor
      Alexandria P. Taylor
      Medicine Design, Pfizer Inc., Groton, Connecticut 06340, United States
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    • Amy L. Brault
      Amy L. Brault
      Medicine Design, Pfizer Inc., Groton, Connecticut 06340, United States
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    • John D. Knafels
      John D. Knafels
      Medicine Design, Pfizer Inc., Groton, Connecticut 06340, United States
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    • Michael L. Vazquez
      Michael L. Vazquez
      Medicine Design, Pfizer Inc., Cambridge, Massachusetts 02139, United States
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    • Gabriel Berstein
      Gabriel Berstein
      Inflammation and Immunology Research, Pfizer Inc., Cambridge, Massachusetts 02139, United States
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    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2023, 14, 2, 191–198
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsmedchemlett.2c00500
    Published January 18, 2023
    Copyright © 2023 American Chemical Society
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    Abstract

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    Macrocyclic retinoic acid receptor-related orphan receptor C2 (RORC2) inverse agonists have been designed with favorable properties for topical administration. Inspired by the unanticipated bound conformation of an acyclic sulfonamide-based RORC2 ligand from cocrystal structure analysis, macrocyclic linker connections between the halves of the molecule were explored. Further optimization of analogues was accomplished to maximize potency and refine physiochemical properties (MW, lipophilicity) best suited for topical application. Compound 14 demonstrated potent inhibition of interleukin-17A (IL-17A) production by human Th17 cells and in vitro permeation through healthy human skin achieving high total compound concentration in both skin epidermis and dermis layers.

    Copyright © 2023 American Chemical Society

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.2c00500.

    • Preparation and characterization data for compounds 7–17, assay descriptions, broad NHR screening for compound 14, and protein crystallography methods (PDF)

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    This article is cited by 2 publications.

    1. Om Darlami, Rabin Pun, Sung-Hoon Ahn, Seok-Ho Kim, Dongyun Shin. Macrocyclization strategy for improving candidate profiles in medicinal chemistry. European Journal of Medicinal Chemistry 2024, 272 , 116501. https://doi.org/10.1016/j.ejmech.2024.116501
    2. Jiuping Zeng, Mingxing Li, Qianyun Zhao, Meijuan Chen, Long Zhao, Shulin Wei, Huan Yang, Yueshui Zhao, Anqi Wang, Jing Shen, Fukuan Du, Yu Chen, Shuai Deng, Fang Wang, Zhuo Zhang, Zhi Li, Tiangang Wang, Shengpeng Wang, Zhangang Xiao, Xu Wu. Small molecule inhibitors of RORγt for Th17 regulation in inflammatory and autoimmune diseases. Journal of Pharmaceutical Analysis 2023, 13 (6) , 545-562. https://doi.org/10.1016/j.jpha.2023.05.009
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    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2023, 14, 2, 191–198
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsmedchemlett.2c00500
    Published January 18, 2023
    Copyright © 2023 American Chemical Society
    Request reuse permissions

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