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Discovery of BMS-986251: A Clinically Viable, Potent, and Selective RORγt Inverse Agonist.
Cherney, Robert J; Cornelius, Lyndon A M; Srivastava, Anurag; Weigelt, Carolyn A; Marcoux, David; Duan, James J-W; Shi, Qing; Batt, Douglas G; Liu, Qingjie; Yip, Shiuhang; Wu, Dauh-Rurng; Ruzanov, Max; Sack, John; Khan, Javed; Wang, Jinhong; Yarde, Melissa; Cvijic, Mary Ellen; Mathur, Arvind; Li, Sha; Shuster, David; Khandelwal, Purnima; Borowski, Virna; Xie, Jenny; Obermeier, Mary; Fura, Aberra; Stefanski, Kevin; Cornelius, Georgia; Tino, Joseph A; Macor, John E; Salter-Cid, Luisa; Denton, Rex; Zhao, Qihong; Carter, Percy H; Dhar, T G Murali.
Affiliation
  • Cherney RJ; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Cornelius LAM; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Srivastava A; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Weigelt CA; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Marcoux D; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Duan JJ; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Shi Q; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Batt DG; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Liu Q; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Yip S; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Wu DR; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Ruzanov M; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Sack J; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Khan J; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Wang J; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Yarde M; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Cvijic ME; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Mathur A; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Li S; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Shuster D; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Khandelwal P; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Borowski V; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Xie J; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Obermeier M; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Fura A; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Stefanski K; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Cornelius G; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Tino JA; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Macor JE; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Salter-Cid L; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Denton R; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Zhao Q; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Carter PH; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
  • Dhar TGM; Bristol Myers Squibb Company, Research and Early Development, Princeton, New Jersey 08540-4000, United States.
ACS Med Chem Lett ; 11(6): 1221-1227, 2020 Jun 11.
Article de En | MEDLINE | ID: mdl-32551004
ABSTRACT
Novel tricyclic analogues were designed, synthesized, and evaluated as RORγt inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound 5, which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound 5 was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound 5 (BMS-986251) was selected as a clinically viable developmental candidate.
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Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Langue: En Journal: ACS Med Chem Lett Année: 2020 Type de document: Article Pays d'affiliation: États-Unis d'Amérique
Texte intégral
Ajouter à My VHL
Imprimer
XML
PubMed Links
Recherche sur Google

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Langue: En Journal: ACS Med Chem Lett Année: 2020 Type de document: Article Pays d'affiliation: États-Unis d'Amérique