Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12.

中文翻译：

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发现片段的小分子用于体内抑制酮己糖激酶（KHK）

果糖的消耗及其后续代谢的增加与人类的肝脂肪变性，血脂异常，肥胖和胰岛素抵抗有关。由于酮己糖激酶（KHK）是负责果糖代谢的主要酶，因此鉴定选择性KHK抑制剂可能有助于进一步阐明KHK抑制作用对这些代谢疾病的影响。迄今为止，由于缺乏可行的体内药理学工具，对小分子抑制KHK的研究一直受到限制。在此我们报告发现12，一种选择性KHK抑制剂，其效力和特性适合评估大鼠模型中的KHK抑制作用。通过基于片段的筛选以及随后使用基于结构的药物设计进行的优化，发现了与KHK相互作用的关键结构特征，平行药物化学鉴定了吡啶12。