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Optimization of Versatile Oxindoles as Selective PI3Kδ Inhibitors.
Methot, Joey L; Achab, Abdelghani; Christopher, Matthew; Zhou, Hua; McGowan, Meredeth A; Trotter, B Wesley; Fradera, Xavier; Lesburg, Charles A; Goldenblatt, Peter; Hill, Armetta; Chen, Dapeng; Otte, Karin M; Augustin, Martin; Shah, Sanjiv; Katz, Jason D.
Afiliación
  • Methot JL; Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • Achab A; Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • Christopher M; Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • Zhou H; Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • McGowan MA; Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • Trotter BW; Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • Fradera X; Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • Lesburg CA; Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • Goldenblatt P; Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • Hill A; Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • Chen D; Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • Otte KM; Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • Augustin M; Proteros Biostructures, Martinsried 82152, Germany.
  • Shah S; Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • Katz JD; Discovery Chemistry, Computational and Structural Chemistry, In Vitro Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
ACS Med Chem Lett ; 11(12): 2461-2469, 2020 Dec 10.
Article en En | MEDLINE | ID: mdl-33335668
ABSTRACT
The 3,3-disubstituted oxindole moiety is a versatile and rigid three-dimensionally shaped scaffold. When engineered with a purine hinge-binding core, exceptionally selective PI3Kδ kinase inhibitors were discovered by exploiting small differences in isoform selectivity pockets. Crystal structures of early lead 2f bound to PI3Kδ and PI3Kα helped rationalize the high selectivity observed with 2f. By attenuating the lypophilicity and metabolic liabilities of an oxindole moiety, we improved the preclinical species PK and solubility and reduced adenosine uptake activity. The excellent potency and kinome selectivity of 7-azaoxindole 4d and spirooxindole 5d, together with a low plasma clearance and good half-life in rat and dog, supported a low once-daily predicted human dose.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos