Discovery of MK-1462: GLP-1 and Glucagon Receptor Dual Agonist for the Treatment of Obesity and Diabetes
Anandan Palani, Andrea R. Nawrocki, Federica Orvieto, Elisabetta Bianchi, Emanuela Mandić, Antonello Pessi, Chunhui Huang, Qiaolin Deng, Nathalie Toussaint, Erika Walsh, Vijay Reddy, Eric R. Ashley, Huaibing He, Sheena Mumick, Brian E. Hawes, Donald J. Marsh, Mark D. Erion, Ravi P. Nargund, Paul E. Carrington
Abstract
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.