GLP-1R PAM

This series of glucagon like peptide-1 receptor (GLP-1R) positive allosteric modulators (PAM) is in lead optimization for type II diabetes. A GLP-1R PAM from this series could become the first orally available small molecule therapeutic agent against this target.

Orally available GLP-1R PAM should increase insulin secretion and decrease blood glucose levels in response to food. We already have discovered and tested orally available GLP-1R PAM in several well-known model of diabetes and confirmed this to be the case.

Most recently, Addex reported that we tested our GLP-1R PAM in “db/db” knockout mice. This is a well known mouse model of diabetes where mice have been genetically modified such that they do not have leptin receptors, the dysfunction of which is believed to be a contributing factor in diabetes. For example, these mice are unable to mount an appropriate insulin response when they receive glucose (sugar) – which results in abnormally high circulating glucose levels and ultimately leads to the development of Type II diabetes; these mice also have hypertension and become obese (like many humans with diabetes).

Addex orally administered our GLP-1R PAM (ADX91886) or sitagliptin (a marketed DPP IV inhibitor, called Januvia) or vehicle placebo to db/db knockout mice. Fifteen minutes later, the mice received 2 g/kg of glucose (orally) and the resulting blood glucose levels were measured. The Addex GLP-1R PAM facilitated a spike in insulin response (see Fig. 1), which resulted in better control over glucose than vehicle control or sitagliptin (see Fig. 2 & 3).