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Azatricyclic Inverse Agonists of RORγt That Demonstrate Efficacy in Models of Rheumatoid Arthritis and Psoriasis

  • Qingjie Liu*
    Qingjie Liu
    Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States
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    Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States
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    Douglas G. Batt
    Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States
    *Phone: 609-252-4034. Email: [email protected]
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    Zili Xiao
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    Michael G. Yang
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    Shailesh Dudhgaonkar
    Biocon Bristol Myers Squibb Research Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India
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    Anjuman Rudra
    Biocon Bristol Myers Squibb Research Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India
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    Nicholas A. Meanwell
    Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States
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    Robert Borzilleri
    Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States
  • , and 
  • T. G. Murali Dhar
    T. G. Murali Dhar
    Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States
Cite this: ACS Med. Chem. Lett. 2021, 12, 5, 827–835
Publication Date (Web):April 30, 2021
https://doi.org/10.1021/acsmedchemlett.1c00112
Copyright © 2021 American Chemical Society
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Supporting Info (1)»

Abstract

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Structure–activity relationship studies directed toward the replacement of the fused phenyl ring of the lead hexahydrobenzoindole RORγt inverse agonist series represented by 1 with heterocyclic moieties led to the identification of three novel aza analogs 57. The hexahydropyrrolo[3,2-f]quinoline series 5 (X = N, Y = Z═CH) showed potency and metabolic stability comparable to series 1 but with improved in vitro membrane permeability and serum free fraction. This structural modification was applied to the hexahydrocyclopentanaphthalene series 3, culminating in the discovery of 8e as a potent and selective RORγt inverse agonist with an excellent in vitro profile, good pharmacokinetic properties, and biologic-like in vivo efficacy in preclinical models of rheumatoid arthritis and psoriasis.

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00112.

  • Experimental details of the preparation and characterization of all target compounds and details of the in vivo evaluation of 8e (PDF)

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