Design, synthesis and biological evaluation of indane derived GPR40 agoPAMs.

GPR40 (FFAR1 or FFA1) is a G protein-coupled receptor, primarily expressed in pancreatic islet β-cells and intestinal enteroendocrine cells. When activated by fatty acids, GPR40 elicits increased insulin secretion from islet β-cells only in the presence of elevated glucose levels. Towards this end, studies were undertaken towards discovering a novel GPR40 Agonist whose mode of action is via Positive Allosteric Modulation of the GPR40 receptor (AgoPAM).

Multivessel Spontaneous Coronary Artery Dissection: Amberen as a Possible Risk Factor.

Spontaneous coronary artery dissection (SCAD) is a rare phenomenon that causes acute, life-threatening myocardial infarction. Most notably occurring in the female population, certain risk factors have been implicated in SCAD including pregnancy, hormone therapy, stimulant drug use, connective tissue disorders and systemic inflammatory disorders. However, the effects of over-the-counter supplements have not been widely studied in SCAD.

Spontaneous Coronary Artery Dissection in a Patient with Undiagnosed Ehlers-Danlos Syndrome.

Spontaneous coronary artery dissection (SCAD) is a rare and deadly cause of acute myocardial infarction (MI). It remains greatly misdiagnosed and carries a high in-hospital mortality rate. Herein, we report a healthy 38-year-old female who presented to our institution for non-ST segment myocardial infarction, in which subsequent coronary angiogram revealed a type 2 spontaneous coronary artery dissection of the obtuse marginal branch with diffuse single-vessel disease of the circumflex artery.

Structure-Activity Relationship of Novel and Selective Biaryl-Chroman GPR40 AgoPAMs.

A series of biaryl chromans exhibiting potent and selective agonism for the GPR40 receptor with positive allosteric modulation of endogenous ligands (AgoPAM) were discovered as potential therapeutics for the treatment of type II diabetes. Optimization of physicochemical properties through modification of the pendant aryl rings resulted in the identification of compound , which possesses an improved metabolic profile while demonstrating sustained glucose lowering.

GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent.

GPR40 agonists are effective antidiabetic agents believed to lower glucose through direct effects on the beta cell to increase glucose stimulated insulin secretion. However, not all GPR40 agonists are the same. Partial agonists lower glucose through direct effects on the pancreas, whereas GPR40 AgoPAMs may incorporate additional therapeutic effects through increases in insulinotrophic incretins secreted by the gut.