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Discovery of potent and efficacious pyrrolopyridazines as dual JAK1/3 inhibitors.
Hynes, John; Wu, Hong; Kempson, James; Duan, James J-W; Lu, Zhonghui; Jiang, Bin; Stachura, Sylwia; Tokarski, John S; Sack, John S; Khan, Javed A; Lippy, Jonathan S; Zhang, Rosemary F; Pitt, Sidney; Shen, Guoxiang; Gillooly, Kate; McIntyre, Kim; Carter, Percy H; Barrish, Joel C; Nadler, Steven G; Salter-Cid, Luisa M; Fura, Aberra; Schieven, Gary L; Pitts, William J; Wrobleski, Stephen T.
Afiliação
  • Hynes J; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA. Electronic address: john.hynes@bms.com.
  • Wu H; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Kempson J; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Duan JJ; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Lu Z; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Jiang B; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Stachura S; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Tokarski JS; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Sack JS; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Khan JA; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Lippy JS; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Zhang RF; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Pitt S; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Shen G; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Gillooly K; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • McIntyre K; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Carter PH; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Barrish JC; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Nadler SG; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Salter-Cid LM; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Fura A; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Schieven GL; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Pitts WJ; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
  • Wrobleski ST; Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
Bioorg Med Chem Lett ; 27(14): 3101-3106, 2017 07 15.
Article em En | MEDLINE | ID: mdl-28539220
A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Piridazinas / Pirróis / Inibidores de Proteínas Quinases / Janus Quinase 1 / Janus Quinase 3 Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Piridazinas / Pirróis / Inibidores de Proteínas Quinases / Janus Quinase 1 / Janus Quinase 3 Idioma: En Ano de publicação: 2017 Tipo de documento: Article