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Triazolopyridine ethers as potent, orally active mGlu2 positive allosteric modulators for treating schizophrenia.
Higgins, Mendi A; Marcin, Lawrence R; Christopher Zusi, F; Gentles, Robert; Ding, Min; Pearce, Bradley C; Easton, Amy; Kostich, Walter A; Seager, Matthew A; Bourin, Clotilde; Bristow, Linda J; Johnson, Kim A; Miller, Regina; Hogan, John; Whiterock, Valerie; Gulianello, Michael; Ferrante, Meredith; Huang, Yanling; Hendricson, Adam; Alt, Andrew; Macor, John E; Bronson, Joanne J.
Afiliación
  • Higgins MA; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA. Electronic address: mendi.higgins@bms.com.
  • Marcin LR; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Christopher Zusi F; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Gentles R; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Ding M; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Pearce BC; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Easton A; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Kostich WA; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Seager MA; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Bourin C; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Bristow LJ; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Johnson KA; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Miller R; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Hogan J; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Whiterock V; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Gulianello M; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Ferrante M; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Huang Y; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Hendricson A; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Alt A; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Macor JE; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
  • Bronson JJ; Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
Bioorg Med Chem ; 25(2): 496-513, 2017 01 15.
Article en En | MEDLINE | ID: mdl-27914948
Triazolopyridine ethers with mGlu2 positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu2 PAMs for the treatment of schizophrenia and merit further preclinical investigation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piridinas / Esquizofrenia / Triazoles / Receptores de Glutamato Metabotrópico / Éteres Límite: Animals Idioma: En Revista: Bioorg Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2017 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piridinas / Esquizofrenia / Triazoles / Receptores de Glutamato Metabotrópico / Éteres Límite: Animals Idioma: En Revista: Bioorg Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2017 Tipo del documento: Article Pais de publicación: Reino Unido