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Development of methyl isoxazoleazepines as inhibitors of BET.
Hewitt, Michael C; Leblanc, Yves; Gehling, Victor S; Vaswani, Rishi G; Côté, Alexandre; Nasveschuk, Christopher G; Taylor, Alexander M; Harmange, Jean-Christophe; Audia, James E; Pardo, Eneida; Cummings, Rich; Joshi, Shivangi; Sandy, Peter; Mertz, Jennifer A; Sims, Robert J; Bergeron, Louise; Bryant, Barbara M; Bellon, Steve; Poy, Florence; Jayaram, Hariharan; Jayaran, Hariharan; Tang, Yong; Albrecht, Brian K.
Afiliación
  • Hewitt MC; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA. Electronic address: mike.hewitt@constellationpharma.com.
  • Leblanc Y; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Gehling VS; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Vaswani RG; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Côté A; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Nasveschuk CG; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Taylor AM; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Harmange JC; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Audia JE; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Pardo E; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Cummings R; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Joshi S; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Sandy P; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Mertz JA; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Sims RJ; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Bergeron L; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Bryant BM; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Bellon S; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Poy F; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Jayaran H; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Tang Y; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
  • Albrecht BK; Constellation Pharmaceuticals, 215 First St., Suite 200, Cambridge, MA 02142, USA.
Bioorg Med Chem Lett ; 25(9): 1842-8, 2015 May 01.
Article en En | MEDLINE | ID: mdl-25851940
ABSTRACT
In this report we detail the evolution of our previously reported thiophene isoxazole BET inhibitor chemotype exemplified by CPI-3 to a novel bromodomain selective chemotype (the methyl isoxazoleazepine chemotype) exemplified by carboxamide 23. The methyl isoxazoleazepine chemotype provides potent inhibition of the bromodomains of the BET family, excellent in vivo PK across species, low unbound clearance, and target engagement in a MYC PK-PD model.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxazoles / Azepinas / Factores de Transcripción / Proteínas Nucleares / Diseño de Fármacos / Proteínas de Unión al ARN / Proteínas Serina-Treonina Quinasas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2015 Tipo del documento: Article
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxazoles / Azepinas / Factores de Transcripción / Proteínas Nucleares / Diseño de Fármacos / Proteínas de Unión al ARN / Proteínas Serina-Treonina Quinasas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2015 Tipo del documento: Article