Your browser doesn't support javascript.
loading
Rationally Designed, Conformationally Constrained Inverse Agonists of RORγt-Identification of a Potent, Selective Series with Biologic-Like in Vivo Efficacy.
Marcoux, David; Duan, James J-W; Shi, Qing; Cherney, Robert J; Srivastava, Anurag S; Cornelius, Lyndon; Batt, Douglas G; Liu, Qingjie; Beaudoin-Bertrand, Myra; Weigelt, Carolyn A; Khandelwal, Purnima; Vishwakrishnan, Sureshbabu; Selvakumar, Kumaravel; Karmakar, Ananta; Gupta, Arun Kumar; Basha, Mushkin; Ramlingam, Sridharan; Manjunath, Naveen; Vanteru, Sridhar; Karmakar, Sukhen; Maddala, Nageswara; Vetrichelvan, Muthalagu; Gupta, Anuradha; Rampulla, Richard A; Mathur, Arvind; Yip, Shiuhang; Li, Peng; Wu, Dauh-Rurng; Khan, Javed; Ruzanov, Max; Sack, John S; Wang, Jinhong; Yarde, Melissa; Cvijic, Mary Ellen; Li, Sha; Shuster, David J; Borowski, Virna; Xie, Jenny H; McIntyre, Kim W; Obermeier, Mary T; Fura, Aberra; Stefanski, Kevin; Cornelius, Georgia; Hynes, John; Tino, Joseph A; Macor, John E; Salter-Cid, Luisa; Denton, Rex; Zhao, Qihong; Carter, Percy H.
Afiliação
  • Marcoux D; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Duan JJ; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Shi Q; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Cherney RJ; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Srivastava AS; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Cornelius L; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Batt DG; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Liu Q; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Beaudoin-Bertrand M; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Weigelt CA; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Khandelwal P; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Vishwakrishnan S; Department of Discovery Synthesis , Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road , Bengaluru 560099 , India.
  • Selvakumar K; Department of Discovery Synthesis , Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road , Bengaluru 560099 , India.
  • Karmakar A; Department of Discovery Synthesis , Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road , Bengaluru 560099 , India.
  • Gupta AK; Department of Discovery Synthesis , Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road , Bengaluru 560099 , India.
  • Basha M; Department of Discovery Synthesis , Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road , Bengaluru 560099 , India.
  • Ramlingam S; Department of Discovery Synthesis , Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road , Bengaluru 560099 , India.
  • Manjunath N; Department of Discovery Synthesis , Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road , Bengaluru 560099 , India.
  • Vanteru S; Department of Discovery Synthesis , Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road , Bengaluru 560099 , India.
  • Karmakar S; Department of Discovery Synthesis , Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road , Bengaluru 560099 , India.
  • Maddala N; Department of Discovery Synthesis , Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road , Bengaluru 560099 , India.
  • Vetrichelvan M; Department of Discovery Synthesis , Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road , Bengaluru 560099 , India.
  • Gupta A; Department of Discovery Synthesis , Biocon Bristol-Myers Squibb Research Centre , Biocon Park, Bommasandra IV Phase, Jigani Link Road , Bengaluru 560099 , India.
  • Rampulla RA; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Mathur A; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Yip S; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Li P; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Wu DR; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Khan J; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Ruzanov M; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Sack JS; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Wang J; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Yarde M; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Cvijic ME; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Li S; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Shuster DJ; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Borowski V; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Xie JH; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • McIntyre KW; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Obermeier MT; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Fura A; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Stefanski K; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Cornelius G; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Hynes J; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Tino JA; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Macor JE; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Salter-Cid L; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Denton R; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Zhao Q; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
  • Carter PH; Research and Development , Bristol-Myers Squibb , 3551 Lawrenceville Rd , Princeton , New Jersey 08540 , United States.
J Med Chem ; 62(21): 9931-9946, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31638797
ABSTRACT
RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.
Assuntos
Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Pirrolidinas / Desenho de Fármacos / Agonismo Inverso de Drogas / Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares Limite: Animais / Humanos Idioma: Inglês Revista: J Med Chem Assunto da revista: Química Ano de publicação: 2019 Tipo de documento: Artigo País de afiliação: Estados Unidos

Similares

MEDLINE

...
LILACS

LIS

Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Pirrolidinas / Desenho de Fármacos / Agonismo Inverso de Drogas / Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares Limite: Animais / Humanos Idioma: Inglês Revista: J Med Chem Assunto da revista: Química Ano de publicação: 2019 Tipo de documento: Artigo País de afiliação: Estados Unidos
...