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Discovery of a novel aminopyrazine series as selective PI3Kα inhibitors.
Barlaam, Bernard; Cosulich, Sabina; Fitzek, Martina; Germain, Hervé; Green, Stephen; Hanson, Lyndsey L; Harris, Craig S; Hancox, Urs; Hudson, Kevin; Lambert-van der Brempt, Christine; Lamorlette, Maryannick; Magnien, Françoise; Ouvry, Gilles; Page, Ken; Ruston, Linette; Ward, Lara; Delouvrié, Bénédicte.
Afiliación
  • Barlaam B; IMED Oncology, AstraZeneca, Darwin Building, Cambridge Science Park, 319 Milton Road, Cambridge CB4 0WG, United Kingdom. Electronic address: bernard.barlaam2@astrazeneca.com.
  • Cosulich S; IMED Oncology, AstraZeneca, Darwin Building, Cambridge Science Park, 319 Milton Road, Cambridge CB4 0WG, United Kingdom.
  • Fitzek M; IMED Oncology, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
  • Germain H; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
  • Green S; IMED Oncology, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
  • Hanson LL; IMED Oncology, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
  • Harris CS; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
  • Hancox U; IMED Oncology, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
  • Hudson K; IMED Oncology, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
  • Lambert-van der Brempt C; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
  • Lamorlette M; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
  • Magnien F; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
  • Ouvry G; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
  • Page K; IMED Oncology, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
  • Ruston L; IMED Oncology, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
  • Ward L; IMED Oncology, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
  • Delouvrié B; AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
Bioorg Med Chem Lett ; 27(13): 3030-3035, 2017 07 01.
Article en En | MEDLINE | ID: mdl-28526367
We report the discovery of a novel aminopyrazine series of PI3Kα inhibitors, designed by hybridizing two known scaffolds of PI3K inhibitors. We describe the progress achieved from the first compounds plagued with poor general kinase selectivity to compounds showing high selectivity for PI3Kα over PI3Kß and excellent general kinase selectivity. This effort culminated with the identification of compound 5 displaying high potency and selectivity, and suitable physiochemical and pharmacokinetic properties for oral administration. In vivo, compound 5 showed good inhibition of tumour growth (86% tumour growth inhibition at 50mg/kg twice daily orally) in the MCF7 xenograft model in mice.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazinas / Inhibidores de Proteínas Quinasas / Descubrimiento de Drogas / Inhibidores de las Quinasa Fosfoinosítidos-3 Límite: Humans Idioma: En Revista: Bioorg Med Chem Lett 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: Pirazinas / Inhibidores de Proteínas Quinasas / Descubrimiento de Drogas / Inhibidores de las Quinasa Fosfoinosítidos-3 Límite: Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2017 Tipo del documento: Article Pais de publicación: Reino Unido