由于其安全性和低成本，二甲双胍已被广泛用于糖尿病治疗。然而，二甲双胍在患者中的药代动力学存在变异性，并且由于其口服吸收差，治疗剂量相对较高，引起不良胃肠反应。因此，在过去几十年中，已合成了二甲双胍的新衍生物。特别是在2000年中期后，有机阳离子转运体被确认为二甲双胍的主要携带者，二甲双胍衍生物接受了密集的研究。然而，由于双胍结构，二甲双胍的衍生物合成具有挑战性。此外，截至目前，二甲双胍的作用机制尚不完全清楚，并且由于其多功能属性，研究兴趣已转向用于其他疾病的再利用。实际上，二甲双胍的衍生物在许多案例中已被证明比二甲双胍本身更有效，并且具有用于不同疾病的潜力，包括多种癌症和神经退行性疾病。另一方面，二甲双胍及其衍生物的多效性性质也可能带来挑战。并非所有的性质都适用于所有疾病。本文综述了二甲双胍类化合物的发展历史，并探讨了其在未来药物发现中的潜力洞见。版权所有 © 2023 Elsevier Inc. 发表。

Metformin has been used for ages to treat diabetes mellitus due to its safety profile and low cost. However, metformin has variable pharmacokinetics in patients, and due to its poor oral absorption, the therapeutic doses are relatively high, causing unpleasant gastrointestinal adverse effects. Therefore, novel derivatives of metformin have been synthesized during the past decades. Particularly, after the mid-2000s, when organic cation transporters were identified as the main metformin carriers, metformin derivatives have been under intensive investigation. Nevertheless, due to the biguanide structure, derivatives of metformin have been challenging to synthesize. Moreover, the mechanisms of metformin's action are not fully understood to date, and since it has multifunctional properties, the interests have switched to re-purposing for other diseases. Indeed, metformin derivatives have been demonstrated in many cases to be more effective than metformin itself and have the potential to be used in different diseases, including several types of cancers and neurodegenerative diseases. On the other hand, the pleiotropic nature of metformin and its derivatives can also create challenges. Not all properties are fit for all diseases. In this review, the history of the development of metformin-like compounds is summarized, and insights into their potential for future drug discovery are discussed.Copyright © 2023. Published by Elsevier Inc.