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Azatricyclic Inverse Agonists of RORγt That Demonstrate Efficacy in Models of Rheumatoid Arthritis and Psoriasis.
Liu, Qingjie; Xiao, Hai-Yun; Batt, Douglas G; Xiao, Zili; Zhu, Yeheng; Yang, Michael G; Li, Ning; Yip, Shiuhang; Li, Peng; Sun, Dawn; Wu, Dauh-Rurng; Ruzanov, Max; Sack, John S; Weigelt, Carolyn A; Wang, Jinhong; Li, Sha; Shuster, David J; Xie, Jenny H; Song, Yunling; Sherry, Tara; Obermeier, Mary T; Fura, Aberra; Stefanski, Kevin; Cornelius, Georgia; Chacko, Silvi; Khandelwal, Purnima; Dudhgaonkar, Shailesh; Rudra, Anjuman; Nagar, Jignesh; Murali, Venkata; Govindarajan, Arun; Denton, Rex; Zhao, Qihong; Meanwell, Nicholas A; Borzilleri, Robert; Dhar, T G Murali.
Afiliação
  • Liu Q; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Xiao HY; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Batt DG; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Xiao Z; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Zhu Y; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Yang MG; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Li N; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Yip S; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Li P; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Sun D; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Wu DR; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Ruzanov M; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Sack JS; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Weigelt CA; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Wang J; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Li S; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Shuster DJ; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Xie JH; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Song Y; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Sherry T; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Obermeier MT; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Fura A; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Stefanski K; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Cornelius G; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Chacko S; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Khandelwal P; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Dudhgaonkar S; Biocon Bristol Myers Squibb Research Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India.
  • Rudra A; Biocon Bristol Myers Squibb Research Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India.
  • Nagar J; Biocon Bristol Myers Squibb Research Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India.
  • Murali V; Biocon Bristol Myers Squibb Research Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India.
  • Govindarajan A; Biocon Bristol Myers Squibb Research Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India.
  • Denton R; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Zhao Q; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Meanwell NA; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Borzilleri R; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • Dhar TGM; Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
ACS Med Chem Lett ; 12(5): 827-835, 2021 May 13.
Article em En | MEDLINE | ID: mdl-34055233
ABSTRACT
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 5-7. 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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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2021 Tipo de documento: Article
Texto completo
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XML
PubMed Links
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2021 Tipo de documento: Article