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Discovery and in Vivo Evaluation of the Potent and Selective PI3Kδ Inhibitors 2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-0687) and 2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-5-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-1430).
Gonzalez-Lopez de Turiso, Felix; Hao, Xiaolin; Shin, Youngsook; Bui, Minna; Campuzano, Iain D G; Cardozo, Mario; Dunn, Michelle C; Duquette, Jason; Fisher, Benjamin; Foti, Robert S; Henne, Kirk; He, Xiao; Hu, Yi-Ling; Kelly, Ron C; Johnson, Michael G; Lucas, Brian S; McCarter, John; McGee, Lawrence R; Medina, Julio C; Metz, Daniela; San Miguel, Tisha; Mohn, Deanna; Tran, Thuy; Vissinga, Christine; Wannberg, Sharon; Whittington, Douglas A; Whoriskey, John; Yu, Gang; Zalameda, Leeanne; Zhang, Xuxia; Cushing, Timothy D.
Afiliación
  • Gonzalez-Lopez de Turiso F; Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Hao X; Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Shin Y; Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Bui M; Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Campuzano ID; Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Cardozo M; Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Dunn MC; Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Duquette J; Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Fisher B; Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Foti RS; Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Henne K; Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • He X; Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Hu YL; Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Kelly RC; Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Johnson MG; Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Lucas BS; Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • McCarter J; Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • McGee LR; Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Medina JC; Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Metz D; Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • San Miguel T; Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Mohn D; Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Tran T; Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Vissinga C; Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Wannberg S; Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Whittington DA; Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Whoriskey J; Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Yu G; Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Zalameda L; Department of Therapeutic Discovery, #Department of Inflammation Research, ⊥Drug Product Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • Zhang X; Department of Therapeutic Discovery, ¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Cushing TD; Department of Therapeutic Discovery, §Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
J Med Chem ; 59(15): 7252-67, 2016 Aug 11.
Article en En | MEDLINE | ID: mdl-27411843
ABSTRACT
Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, 4, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 6a (AM-0687) and 7 (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of 6a and 7 in biochemical and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin model in rats demonstrated that administration of either 6a or 7 resulted in a strong dose-dependent reduction of IgG and IgM specific antibodies. The excellent in vitro and in vivo profiles of these analogs make them suitable for further development.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piridinas / Quinolinas / Inhibidores de Proteínas Quinasas / Descubrimiento de Drogas / Inhibidores de las Quinasa Fosfoinosítidos-3 Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piridinas / Quinolinas / Inhibidores de Proteínas Quinasas / Descubrimiento de Drogas / Inhibidores de las Quinasa Fosfoinosítidos-3 Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos
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