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Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis.
Tamayo, Nuria A; Norman, Mark H; Bartberger, Michael D; Hong, Fang-Tsao; Bo, Yunxin; Liu, Longbin; Nishimura, Nobuko; Yang, Kevin C; Tadesse, Seifu; Fotsch, Christopher; Chen, Jie; Chmait, Samer; Cupples, Rod; Hale, Clarence; Jordan, Steven R; Lloyd, David J; Sivits, Glenn; Van, Gwyneth; St Jean, David J.
Afiliação
  • Tamayo NA; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
  • Norman MH; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
  • Bartberger MD; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
  • Hong FT; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
  • Bo Y; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
  • Liu L; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
  • Nishimura N; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
  • Yang KC; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
  • Tadesse S; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
  • Fotsch C; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
  • Chen J; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
  • Chmait S; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
  • Cupples R; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
  • Hale C; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
  • Jordan SR; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
  • Lloyd DJ; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
  • Sivits G; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
  • Van G; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
  • St Jean DJ; †Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Tho
J Med Chem ; 58(11): 4462-82, 2015 Jun 11.
Article em En | MEDLINE | ID: mdl-25914941
ABSTRACT
The glucokinase-glucokinase regulatory protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis in the liver. We have recently disclosed a series of arylpiperazines as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure-activity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone 93, which was able to disrupt the GK-GKRP interaction in vitro and in vivo and, by doing so, increases cytoplasmic levels of unbound GK.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sulfonas / Proteínas de Transporte / Bibliotecas de Moléculas Pequenas / Glucoquinase / Aminopiridinas / Hipoglicemiantes / Fígado Limite: Animals Idioma: En Ano de publicação: 2015 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sulfonas / Proteínas de Transporte / Bibliotecas de Moléculas Pequenas / Glucoquinase / Aminopiridinas / Hipoglicemiantes / Fígado Limite: Animals Idioma: En Ano de publicação: 2015 Tipo de documento: Article