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Potent benzoazepinone γ-secretase modulators with improved bioavailability.
Methot, Joey L; Fischer, Christian; Li, Chaomin; Rivkin, Alexey; Ahearn, Sean P; Brown, William Colby; Kattar, Sam; Kelley, Elizabeth; Mampreian, Dawn M; Schell, Adam; Rosenau, Andrew; Zhou, Hua; Ball, Richard; Deshmukh, Sujal V; Jeliazkova-Mecheva, Valentina V; Diaz, Damaris; Moy, Lily Y; Kenific, Candia M; Moxham, Chris; Shah, Sanjiv; Nuthall, Hugh; Szewczak, Alexander A; Hill, Armetta; Hughes, Bethany; Smotrov, Nadya; Munoz, Benito; Miller, Thomas A; Shearman, Mark S.
Afiliación
  • Methot JL; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: joey_methot@merck.com.
  • Fischer C; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Li C; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Rivkin A; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Ahearn SP; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Brown WC; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Kattar S; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Kelley E; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Mampreian DM; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Schell A; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Rosenau A; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Zhou H; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Ball R; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Deshmukh SV; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Jeliazkova-Mecheva VV; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Diaz D; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Moy LY; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Kenific CM; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Moxham C; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Shah S; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Nuthall H; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Szewczak AA; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Hill A; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Hughes B; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Smotrov N; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Munoz B; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Miller TA; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Shearman MS; Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Bioorg Med Chem Lett ; 25(17): 3495-500, 2015 Sep 01.
Article en En | MEDLINE | ID: mdl-26142947
ABSTRACT
The triazolyl amide γ-secretase modulators are potent alternatives to the cinnamyl amides that have entered the clinic for the treatment of Alzheimer's disease. Herein we build on the lead benzoazepinones described in our prior communication with imidazomethoxyarene moiety alternatives that offer opportunities to fine tune physical properties as well as address hERG binding and PK. Both half-life and bioavailability were significantly improved, especially in dog, with robust brain Aß42 lowering maintained in both transgenic mouse and rat.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Secretasas de la Proteína Precursora del Amiloide / Enfermedad de Alzheimer Límite: Animals Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2015 Tipo del documento: Article
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Secretasas de la Proteína Precursora del Amiloide / Enfermedad de Alzheimer Límite: Animals Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2015 Tipo del documento: Article