葡萄糖激酶-葡萄糖激酶调节蛋白相互作用的小分子干扰物：5. 新型芳基砜系列，通过构象分析进行优化。
Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis.
作者信息
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
机构信息
†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.
出版信息
J Med Chem. 2015 Jun 11;58(11):4462-82. doi: 10.1021/jm5018175. Epub 2015 Jun 1.
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describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group.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.
葡萄糖激酶-葡萄糖激酶调节蛋白（GK-GKRP）复合物在控制肝脏葡萄糖稳态中起重要作用。我们最近披露了一系列芳基哌嗪作为GK-GKRP复合物的体外和体内破坏剂，在2型糖尿病（T2DM）啮齿动物模型中具有疗效。在此，我们描述了一类新型的芳基砜作为GK-GKRP复合物的破坏剂，其中央哌嗪骨架已被芳基取代。对这类新化合物的构象分析和构效关系探索导致了强效GK-GKRP破坏剂的鉴定。对这一新系列的进一步优化得到了噻唑砜93，其能够在体外和体内破坏GK-GKRP相互作用，并通过这样做增加未结合GK的细胞质水平。
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