小分子胰岛素增敏剂：下一代胰岛素增敏策略的新线索和靶点

摘要(中文译文)

2型糖尿病（T2D）是一个重大的全球健康问题，其主要驱动因素是胰岛素抵抗，即细胞对胰岛素的反应受损。目前很少有疗法能够直接针对这一根本病因。噻唑烷二酮类药物是强效的过氧化物酶体增殖物激活受体γ（PPARγ）激动剂，仍是唯一真正的小分子胰岛素增敏剂，但其临床应用受到与该靶点非选择性激活相关的不良反应的限制。因此，研究已转向不依赖PPARγ激动作用而增强胰岛素信号传导的替代途径。本综述总结了2013年至2025年间，在多种不同骨架和机制的新型小分子胰岛素增敏剂开发方面取得的进展。重点阐述了构效关系、已确立和新兴的分子靶点，以及为合理药物设计提供依据的结构学见解。此外，还采用BOILED-Egg模型对部分先导化合物进行了评估，以评价其口服药物相似性和早期“技术成熟度”。总体而言，本综述旨在通过展示有前景的先导化合物和策略，为下一代胰岛素增敏疗法的开发提供启发，以激励药物化学家。

Abstract

Type 2 diabetes (T2D) is a major global health problem driven largely by insulin resistance, the impaired cellular response to insulin. Few current therapies directly address this underlying cause. Thiazolidinediones, potent peroxisome proliferator-activated receptor gamma (PPARγ) agonists, remain the only true small-molecule insulin sensitisers, but their clinical use is limited by adverse effects associated with non-selective activation of this target. Consequently, research has shifted toward alternative pathways that enhance insulin signalling without relying on PPARγ agonism. This review summarises advances from 2013 to 2025 in the development of novel small-molecule insulin sensitisers across diverse scaffolds and mechanisms. Structure-activity relationships, established and emerging molecular targets, and structural insights that inform rational drug design are highlighted. Selected leads were also evaluated using the BOILED-Egg model to assess oral drug-likeness and early "technology readiness." Overall, this review aims to inspire medicinal chemists by presenting promising leads and strategies for the development of next-generation insulin-sensitising therapeutics.

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