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 receptor partial agonists
(IRPAs) with a potential to mitigate the risk of hypoglycemia associated
with the use of insulin as an antidiabetic treatment. These molecules
were designed as dimers of native insulin connected via chemical linkers
of variable lengths with optional capping groups at the N-terminals
of insulin chains. Depending on the structure, the maximal activation
level (%Max) varied in the range of ∼20–70% of native
insulin, and EC50 values remained in sub-nM range. Studies
in minipig and dog demonstrated that IRPAs had sufficient efficacy
to normalize plasma glucose levels in diabetes, while providing reduction
of hypoglycemia risk. IRPAs had a prolonged duration of action, potentially
making them suitable for once-daily dosing. Two lead compounds with
%Max values of 30 and 40% relative to native insulin were selected
for follow up studies in the clinic.