Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark.
Drugs. 2019 Jul;79(11):1187-1197. doi: 10.1007/s40265-019-01153-6.
Obesity, type 2 diabetes, and the numerous associated metabolic co-morbidities are growing global threats to public health. Despite recent progress in pharmacotherapies for metabolic diseases, the current treatment options have limited efficacy and provide mostly symptomatic relief with little or no impact on disease reversal. Thus, improved therapies are urgently needed. As a result, the scientific community has increasingly invested in leveraging new pathophysiological insights into more efficacious pharmacotherapies for metabolic complications. A heightened understanding of the large, interindividual variation in responsiveness to certain metabolic medicines combined with advances in engineering multi-agonist candidates are important steps towards this goal. Additionally, the emerging pharmacological concept of peptide-mediated targeting of small molecules for tissue-specific delivery holds promise for more powerful treatment solutions in the future. In this review, we summarize recent advances in medicinal chemistry and molecular pharmacology that have enabled the engineering of several, novel, poly-agonist drug candidates for treatment of metabolic diseases, and we discuss the recent results from clinical trials assessing the efficacy and safety of glucagon-like peptide (GLP)-1/glucagon and GLP-1/GIP co-agonists.
肥胖症、2 型糖尿病以及众多相关代谢合并症是对全球公众健康的日益严重的威胁。尽管代谢疾病的药物治疗最近取得了进展，但目前的治疗选择疗效有限，只能提供对症缓解，对疾病逆转几乎没有影响。因此，迫切需要改进的治疗方法。因此，科学界越来越多地投资于利用新的病理生理学见解，开发更有效的代谢并发症药物治疗方法。深入了解对某些代谢药物的反应存在较大个体间差异，再加上工程多激动剂候选药物的进展，是实现这一目标的重要步骤。此外，小分子肽介导的靶向递药的新兴药理学概念为未来更强大的治疗解决方案提供了希望。在这篇综述中，我们总结了药物化学和分子药理学的最新进展，这些进展使几种新型多激动剂药物候选物的工程设计成为可能，用于治疗代谢疾病，我们还讨论了最近评估胰高血糖素样肽 (GLP)-1/胰高血糖素和 GLP-1/GIP 双重激动剂疗效和安全性的临床试验结果。
