Palani Anandan, Nawrocki Andrea R, Orvieto Federica, Bianchi Elisabetta, Mandić Emanuela, Pessi Antonello, Huang Chunhui, Deng Qiaolin, Toussaint Nathalie, Walsh Erika, Reddy Vijay, Ashley Eric, He Huaibing, Mumick Sheena, Hawes Brian, Marsh Donald, Erion Mark, Nargund Ravi, Carrington Paul E
Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 United States.
Peptide Chemistry Unit, Peptides and Small Molecules R&D, IRBM SpA, Via Pontina, Km 30.600, 00071 Roma, Italy.
ACS Med Chem Lett. 2022 Jul 21;13(8):1248-1254. doi: 10.1021/acsmedchemlett.2c00217. eCollection 2022 Aug 11.
Peptide-based analogues of the gut-derived incretin hormone, glucagon-like peptide 1 (GLP1), stimulate insulin secretion in a glucose-dependent manner. Currently marketed GLP1 receptor (GLP1R) agonists are safe and effective in the management of Type 2 diabetes but often offer only modest weight loss. This has prompted the search for safe and effective alternatives to enhance the weight loss component of these treatments. We have demonstrated that concomitant activation GLP1R and the glucagon receptor (GCGR) can improve glucose metabolism and provide superior weight loss when compared to selective GLP1R agonism in preclinical species. This paper will highlight chemistry structure-activity relationship optimization and summarize in vivo efficacy studies toward the discovery of a once daily balanced dual agonist (MK-1462), which was advanced into clinical trials.
肠道来源的肠促胰岛素激素胰高血糖素样肽1（GLP1）的肽基类似物以葡萄糖依赖的方式刺激胰岛素分泌。目前上市的GLP1受体（GLP1R）激动剂在2型糖尿病的管理中是安全有效的，但通常只能带来适度的体重减轻。这促使人们寻找安全有效的替代方案，以增强这些治疗方法中的体重减轻效果。我们已经证明，与临床前物种中的选择性GLP1R激动作用相比，同时激活GLP1R和胰高血糖素受体（GCGR）可以改善葡萄糖代谢并实现更显著的体重减轻。本文将重点介绍化学结构-活性关系的优化，并总结针对每日一次平衡双激动剂（MK-1462）发现的体内疗效研究，该双激动剂已进入临床试验阶段。
