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Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis. 2015
Nuria A Tamayo, and
Mark H Norman, and
Michael D Bartberger, and
Fang-Tsao Hong, and
Yunxin Bo, and
Longbin Liu, and
Nobuko Nishimura, and
Kevin C Yang, and
Seifu Tadesse, and
Christopher Fotsch, and
Jie Chen, and
Samer Chmait, and
Rod Cupples, and
Clarence Hale, and
Steven R Jordan, and
David J Lloyd, and
Glenn Sivits, and
Gwyneth Van, and
David J St Jean
†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, Thousand Oaks, California 91320, United States.
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describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group.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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Fang-Tsao Hong, and
Yunxin Bo, and
Longbin Liu, and
Nobuko Nishimura, and
Kevin C Yang, and
Seifu Tadesse, and
Christopher Fotsch, and
Jie Chen, and
Samer Chmait, and
Rod Cupples, and
Clarence Hale, and
Steven R Jordan, and
David J Lloyd, and
Glenn Sivits, and
Gwyneth Van, and
David J St Jean
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Glenn Sivits, and
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Kevin C Yang, and
Seifu Tadesse, and
Christopher Fotsch, and
Jie Chen, and
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Rod Cupples, and
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Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents,
