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@ARTICLE{Orsi:491342,
      author       = {Orsi, Douglas L. and Ferrara, Steven J. and Siegel, Stephan
                      and Friberg, Anders and Bouché, Léa and Pook, Elisabeth
                      and Lienau, Philip and Bluck, Joseph P. and Lemke,
                      Christopher T. and Akcay, Gizem and Stellfeld, Timo and
                      Meyer, Hanna and Pütter, Vera and Holton, Simon J. and
                      Korr, Daniel and Jerchel-Furau, Isabel and Pantelidou,
                      Constantia and Strathdee, Craig A. and Meyerson, Matthew and
                      Eis, Knut and Goldstein, Jonathan T.},
      title        = {{D}iscovery and characterization of orally bioavailable
                      4-chloro-6-fluoroisophthalamides as covalent {PPARG}
                      inverse-agonists},
      journal      = {Bioorganic $\&$ medicinal chemistry},
      volume       = {78},
      issn         = {0968-0896},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {PUBDB-2023-00097},
      pages        = {117130},
      year         = {2023},
      abstract     = {PPAR gamma (PPARG) is a ligand activated transcription
                      factor that regulates genes involved in inflammation, bone
                      biology, lipid homeostasis, as well as a master regulator of
                      adipogenesis and a potential lineage driver of luminal
                      bladder cancer. While PPARG agonists lead to transcriptional
                      activation of canonical target genes, inverse agonists have
                      the opposite effect through inducing a transcriptionally
                      repressive complex leading to repression of canonical target
                      gene expression. While many agonists have been described and
                      tested clinically, inverse agonists offer an underexplored
                      avenue to modulate PPARG biology in vivo. Current inverse
                      agonists lack favorable in vivo properties; herein we
                      describe the discovery and characterization of a series of
                      orally bioavailable 4-chloro-6-fluoroisophthalamides as
                      covalent PPARG inverse-agonists, BAY-5516, BAY-5094, and
                      BAY-9683. Structural studies of this series revealed
                      distinct pre- and post-covalent binding positions, which led
                      to the hypothesis that interactions in the pre-covalent
                      conformation are primarily responsible for driving affinity,
                      while interactions in the post-covalent conformation are
                      more responsible for cellular functional effects by
                      enhancing PPARG interactions with its corepressors. The need
                      to simultaneously optimize for two distinct states may
                      partially explain the steep SAR observed. Exquisite
                      selectivity was achieved over related nuclear receptors in
                      the subfamily due in part to a covalent warhead with low
                      reactivity through an SNAr mechanism in addition to the
                      specificity gained through covalent binding to a reactive
                      cysteine uniquely positioned within the PPARG LBD. BAY-5516,
                      BAY-5094, and BAY-9683 lead to pharmacodynamic regulation of
                      PPARG target gene expression in vivo comparable to known
                      inverse agonist SR10221 and represent new tools for future
                      in vivo studies to explore their potential utility for
                      treatment of disorders of hyperactivated PPARG including
                      luminal bladder cancer and other disorders.},
      cin          = {EMBL-User},
      ddc          = {610},
      cid          = {I:(DE-H253)EMBL-User-20120814},
      pnm          = {6G3 - PETRA III (DESY) (POF4-6G3)},
      pid          = {G:(DE-HGF)POF4-6G3},
      experiment   = {EXP:(DE-H253)P-P14-20150101 / EXP:(DE-H253)P-P11-20150101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {36542958},
      UT           = {WOS:000911046100001},
      doi          = {10.1016/j.bmc.2022.117130},
      url          = {https://bib-pubdb1.desy.de/record/491342},
}