Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose

Increased fructose
consumption and its subsequent metabolism have
been implicated in metabolic disorders such as nonalcoholic fatty
liver disease and steatohepatitis (NAFLD/NASH) and insulin resistance.
Ketohexokinase (KHK) converts fructose to fructose-1-phosphate (F1P)
in the first step of the metabolic cascade. Herein we report the discovery
of a first-in-class KHK inhibitor, PF-06835919 (8), currently
in phase 2 clinical trials. The discovery of 8 was built
upon our originally reported, fragment-derived lead 1 and the recognition of an alternative, rotated binding mode upon
changing the ribose-pocket binding moiety from a pyrrolidinyl to an
azetidinyl ring system. This new binding mode enabled efficient exploration
of the vector directed at the Arg-108 residue, leading to the identification
of highly potent 3-azabicyclo[3.1.0]­hexane acetic acid-based KHK inhibitors
by combined use of parallel medicinal chemistry and structure-based
drug design.

果糖摄入量增加及其后续代谢过程，已被证实与非酒精性脂肪性肝病（NAFLD）、脂肪性肝炎（NASH）及胰岛素抵抗等代谢紊乱存在关联。己酮糖激酶（KHK）可在代谢级联反应的第一步中将果糖转化为1-磷酸果糖（F1P）。本研究报道了同类首创KHK抑制剂PF-06835919（化合物8）的发现历程，该药物目前正处于II期临床试验阶段。化合物8的研发基于本团队此前报道的片段衍生先导化合物1，以及一项新的结合模式认知：当核糖口袋的结合基团从吡咯烷基环系替换为氮杂环丁烷基环系时，会产生一种全新的旋转型结合模式。这种全新的结合模式使得针对精氨酸-108（Arg-108）残基的导向矢量得以高效探索，最终通过平行药物化学与基于结构的药物设计联用策略，成功发现了强效的3-氮杂双环[3.1.0]己烷乙酸类KHK抑制剂。