Discovery of MK-1462: GLP‑1 and Glucagon Receptor Dual Agonist for the Treatment of Obesity and Diabetes

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.

肠道源肠促胰岛素激素胰高血糖素样肽1（GLP1）的肽类类似物，可通过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2型糖尿病的管理中安全有效，但通常仅能实现轻度体重减轻。这推动了对安全有效替代方案的探索，以强化此类疗法的减重效果。本团队已证实，在临床前物种中，同时激活GLP1受体与胰高血糖素受体（GCGR），相较于选择性GLP1受体激动，可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-活性关系优化工作，并总结体内药效研究，旨在开发一款每日一次的平衡型双靶点激动剂12（MK-1462），该化合物已推进至临床试验阶段。