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Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFα Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches.
Xiao, Hai-Yun; Li, Ning; Duan, James J-W; Jiang, Bin; Lu, Zhonghui; Ngu, Khehyong; Tino, Joseph; Kopcho, Lisa M; Lu, Hao; Chen, Jing; Tebben, Andrew J; Sheriff, Steven; Chang, ChiehYing Y; Yanchunas, Joseph; Calambur, Deepa; Gao, Mian; Shuster, David J; Susulic, Vojkan; Xie, Jenny H; Guarino, Victor R; Wu, Dauh-Rurng; Gregor, Kurt R; Goldstine, Christine B; Hynes, John; Macor, John E; Salter-Cid, Luisa; Burke, James R; Shaw, Patrick J; Dhar, T G Murali.
Afiliação
  • Xiao HY; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Li N; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Duan JJ; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Jiang B; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Lu Z; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Ngu K; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Tino J; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Kopcho LM; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Lu H; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Chen J; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Tebben AJ; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Sheriff S; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Chang CY; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Yanchunas J; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Calambur D; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Gao M; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Shuster DJ; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Susulic V; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Xie JH; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Guarino VR; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Wu DR; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Gregor KR; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Goldstine CB; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Hynes J; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Macor JE; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Salter-Cid L; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Burke JR; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Shaw PJ; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • Dhar TGM; Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
J Med Chem ; 63(23): 15050-15071, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33261314
ABSTRACT
Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.
Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Tipo de estudo: Estudo prognóstico Idioma: Inglês Revista: J Med Chem Assunto da revista: Química Ano de publicação: 2020 Tipo de documento: Artigo País de afiliação: Estados Unidos

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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Tipo de estudo: Estudo prognóstico Idioma: Inglês Revista: J Med Chem Assunto da revista: Química Ano de publicação: 2020 Tipo de documento: Artigo País de afiliação: Estados Unidos