Novel EP3 Antagonists to treat Type II Diabetes (T2DM)
Type II Diabetes Mellitus (T2DM) is a complex metabolic disorder characterized by β-cell failure in the setting of insulin resistance. Hyperglycemia and elevated levels of free fatty acids (FFAs) contribute to β-cell dysfunction and their subsequent death, leading to decreased β-cell mass. To date, T2DM therapies focus on either increasing peripheral insulin sensitivity, Sodium-Glucose co-transporters 2 (SGLT2) inhibitors, by increasing insulin secretion, (GLP-1 analogs, GLP1 receptor agonists (GLP1-Ras daily/weekly injections) or DPP4 inhibitors (pills/ inhibit the degradation of GLP-1).
However, there is a dire need to identify new pathways which are involved in the deterioration of β-cell function and survival, and find ways to block these pathways in order to delay the progression of the disease.
EP3 receptor was found to be upregulated in human islets isolated from T2DM patients compared to non-diabetic individuals and is upregulated by fatty acids which have an essential role in the development of insulin resistance and T2DM. This discovery led to the development of a unique in silico high throughput screening, conducted in collaboration with Prof. Amiram Goldblum of the Hebrew University, which resulted in the identification of several novel small molecules as EP3 antagonists, out of 2.5 million screened compounds.
The synthesized molecules were shown to:
– restore glucose-stimulated insulin secretion and content in vitro and ex vivo in human islet β cells.
– improve glycemia, with no toxic effect on liver or kidney functions in vivo in a T2DM mouse model
– significantly decrease insulin resistance and triglycerides levels which are associated with cardiovascular diseases.
– present superiority in glucose tolerance compared to the commonly used GLP1-RA Liraglutide (Victoza®).
To summarize, the novel EP3 antagonist molecules improve both the function and survival of β-cells as well as insulin sensitivity in insulin-target tissues leading to the observed improved glycemia.
The current study focuses on assessing the compound’s effect on the β-cell mass.
IP is being filed in US, EU and Israel. PCT Publication No. WO/2022/215072
The CDC states that diabetes affects ~37 million Americans, with T2DM accounting for as high as 95% of cases. The global type 2 diabetes market was valued at $29.81Bn, with a significant CAGR of over 8% within the next decade, due in part to the global obesity epidemic.