Discovery of Insulin Receptor Partial Agonists MK-5160 and MK-1092 as Novel Basal Insulins with Potential to Improve Therapeutic Index

We have identified a series of novel insulin receptorpartial agonists (IRPAs) with a potential to mitigate the risk ofhypoglycemia associated with the use of insulin as an antidiabetictreatment. These molecules were designed as dimers of nativeinsulin connected via chemical linkers of variable lengths withoptional capping groups at the N-terminals of insulin chains.Depending on the structure, the maximal activation level (%Max)varied in the range of similar to 20-70% of native insulin, and EC50valuesremained in sub-nM range. Studies in minipig and dogdemonstrated that IRPAs had sufficient efficacy to normalizeplasma glucose levels in diabetes, while providing reduction ofhypoglycemia risk. IRPAs had a prolonged duration of action,potentially making them suitable for once-daily dosing. Two leadcompounds with %Max values of 30 and 40% relative to native insulin were selected for follow up studies in the clinic.

Automated summary

We have identified a series of novel insulin receptor partial agonists (IRPAs) that have the potential to reduce the risk of hypoglycemia associated with insulin treatment for diabetes. These compounds are designed as dimers of native insulin and have shown favorable activation levels within the sub-nanomolar range. Animal studies have demonstrated that these compounds effectively regulate blood glucose levels in diabetes, while reducing the risk of hypoglycemia. Two lead compounds with relative activation levels of 30% and 40% have been selected for further clinical studies.