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Discovery of MK-1462: GLP-1 and Glucagon Receptor Dual Agonist for the Treatment of Obesity and Diabetes
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2022-07-21 , DOI: 10.1021/acsmedchemlett.2c00217 Anandan Palani 1 , Andrea R Nawrocki 1 , Federica Orvieto 2 , Elisabetta Bianchi 2 , Emanuela Mandić 2 , Antonello Pessi 3 , Chunhui Huang 1 , Qiaolin Deng 1 , Nathalie Toussaint 1 , Erika Walsh 1 , Vijay Reddy 1 , Eric Ashley 1 , Huaibing He 1 , Sheena Mumick 1 , Brian Hawes 1 , Donald Marsh 1 , Mark Erion 1 , Ravi Nargund 1 , Paul E Carrington 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2022-07-21 , DOI: 10.1021/acsmedchemlett.2c00217 Anandan Palani 1 , Andrea R Nawrocki 1 , Federica Orvieto 2 , Elisabetta Bianchi 2 , Emanuela Mandić 2 , Antonello Pessi 3 , Chunhui Huang 1 , Qiaolin Deng 1 , Nathalie Toussaint 1 , Erika Walsh 1 , Vijay Reddy 1 , Eric Ashley 1 , Huaibing He 1 , Sheena Mumick 1 , Brian Hawes 1 , Donald Marsh 1 , Mark Erion 1 , Ravi Nargund 1 , Paul E Carrington 1
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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 12 (MK-1462), which was advanced into clinical trials.
中文翻译：
MK-1462 的发现：用于治疗肥胖和糖尿病的 GLP-1 和胰高血糖素受体双重激动剂
肠源性肠促胰岛素激素的肽类似物胰高血糖素样肽 1 (GLP1) 以葡萄糖依赖性方式刺激胰岛素分泌。目前上市的 GLP1 受体 (GLP1R) 激动剂在治疗 2 型糖尿病方面安全有效，但通常只能实现适度的减肥效果。这促使人们寻找安全有效的替代方案来增强这些治疗的减肥效果。我们已经证明，在临床前物种中，与选择性 GLP1R 激动相比，同时激活 GLP1R 和胰高血糖素受体 (GCGR) 可以改善葡萄糖代谢并提供更好的减肥效果。本文将重点介绍化学结构-活性关系的优化，并总结体内功效研究，以发现每日一次的平衡双激动剂12 (MK-1462)，该药物已进入临床试验。
更新日期：2022-07-21
中文翻译：
MK-1462 的发现：用于治疗肥胖和糖尿病的 GLP-1 和胰高血糖素受体双重激动剂
肠源性肠促胰岛素激素的肽类似物胰高血糖素样肽 1 (GLP1) 以葡萄糖依赖性方式刺激胰岛素分泌。目前上市的 GLP1 受体 (GLP1R) 激动剂在治疗 2 型糖尿病方面安全有效，但通常只能实现适度的减肥效果。这促使人们寻找安全有效的替代方案来增强这些治疗的减肥效果。我们已经证明，在临床前物种中，与选择性 GLP1R 激动相比，同时激活 GLP1R 和胰高血糖素受体 (GCGR) 可以改善葡萄糖代谢并提供更好的减肥效果。本文将重点介绍化学结构-活性关系的优化，并总结体内功效研究，以发现每日一次的平衡双激动剂12 (MK-1462)，该药物已进入临床试验。
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