“The incidence of type 2 diabetes (T2D) has increased significantly in recent years, becoming a serious health care problem, with an estimated 285 million cases worldwide and an expected 439 million by the year 2030. Although several oral treatments for type two diabetes mellitus are available, some of them have been associated with undesired adverse effects such as hypoglycemia, liver damage, gastrointestinal disease and weight gain. Therefore new treatment options offering a more desirable safety profile through novel mechanism-based treatment methods are desired to effectively treat or prevent diabetes in more patients. The G protein-coupled receptor, GPR40, also known as FFA1 or FFAR1 (Free Fatty Acid Receptor 1) is highly expressed in pancreatic beta cell and responds to endogenous fatty acids resulting in amplification of insulin secretion only in the presence of elevated glucose levels. The glucose dependency of insulin secretion makes this receptor an excellent target for developing efficacious therapies with a desired safety profile for use in the treatment of T2D. We wish to report the discovery of a novel class of G protein coupled receptor 40 agonists for the treatment of type 2 diabetes. Hypothesis driven structural modifications to the endogenous ligands FFAs led to the identification of spiropiperidine acid derivatives with unique pharmacokinetic properties. Of these, we have characterized compounds that can preferentially signal either through the G protein- or b-arrestin-dependent pathways. We have the SAR of these GPR40 biased ligands to better understand the role of G protein and β-arrestin-mediated signaling on the in vivo efficacy. In our hands GPR40 b-arrestin activity helps to more accurately predict the affinity of agonists to the receptor and demonstrated a better correlation with in vivo efficacy. Compounds with strong engagement of b-arrestins at GPR40 receptor such as LY2881835 demonstrated the highest affinity for human GPR40, stimulated GDIS in rodent and human primary islets and showed the most potent glucose lowering during ipGTT in normal mice and during OGTT in a rodent model of insulin resistance. No desensitization of GPR40 was seen after 21 days of oral administration to Zucker fa/fa rats. The unique pharmacology and pharmacokinetic properties promised further development of these compounds as potential anti-diabetic drug candidates. Preclinical and early clinical data will be discussed.

Novel GPR40 agonists for the treatment of type-2 diabetes: The effect of b-arrestin signaling

249th National Meeting (2015)

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