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br Conclusion In summary a series of novel
Conclusion
In summary, a series of novel GPR40 agonists bearing phenylpropiolic Protein A/G motif with favorable metabolic stability were prepared and evaluated for their activities as GPR40 agonists. Among them, compound 9 was identified as a structurally distinct GPR40 agonist possessing potent activity in vitro, and was effective in cellular insulin secretion in MIN6 cells under high-glucose conditions which could be reversed by a selective GPR40 antagonist GW1100. In vivo, compound 9 significantly lowered plasma glucose levels in normal mice during an oral glucose tolerance test suggesting that this compound served as a valuable research tool to explore the therapeutic utility of GPR40 agonists.
Experimental section
The consequences of diabetes are severe and far-reaching. Despite the development of multiple therapeutic options in the decades since the introduction of isolated insulin first revolutionized the treatment of diabetes, complications from inadequately controlled diabetes still inflict blindness, kidney failure, amputations, and death upon thousands of patients every year. Alongside the staggering human costs of diabetes stands the burden on overstretched healthcare systems worldwide. As of 2002, 11% of all direct healthcare costs were due to diabetes and its associated co-morbidities. This burden is only expected to increase with the spread of sedentary lifestyles and the “western diet” leading to an estimated 366 million diabetics worldwide by the year 2030 [1].
Diabetes is classically characterized by an inability of the patient to maintain glucose homeostasis. This defect arises due to both increased resistance of bodily tissues to the effects of insulin as well as a marked decrease in secretion of insulin by the pancreatic islets in response to glucose. Therapeutic agents targeting the latter of these two defects, insulin secretagogues, have been in use for nearly 50 years. Still in wide use, sulfonylurea insulin secretagogues target the ATP-sensitive potassium (KATP) channel present in pancreatic beta cells and elicit a sustained elevation in insulin release [2]. However, a drawback associated with the use of sulfonylurea insulin secretagogues is that their activity is not modulated by the plasma glucose level in the patient. Continued insulin secretion during periods of relatively low blood sugar such as an extended break between meals or vigorous exercise leads to hypoglycemia with its attendant symptoms of sweating, nervousness, dizziness, and confusion. Without intervention, patients can lose consciousness or even fall comatose. Newer generation therapeutics targeting the KATP channel such as the glinides seek to avoid the risk of hypoglycemia by acting for a short period of time. When taken shortly before or with a meal, the shorter acting insulin secretagogues provide a surge of insulin that allows glucose and other nutrients to be absorbed by body tissues but then the relatively rapid clearance of these compounds leads to a cessation of secretagogue activity [3].
An elegant solution to the risk of hypoglycemia would be for the activity of the insulin secretagogue to be dependent upon elevated plasma glucose levels. Glucagon-like peptide 1 (GLP-1) receptor-based therapeutics have shown just such activity [4]. While GLP-1 itself is unsuitable as a therapeutic agent due to its short half-life, a variety of peptide analogs have been developed clinically. One in particular, exenatide, won approval by the United States Food and Drug Administration (FDA) in 2005 [4]. The peptidic nature of GLP-1 and its analogs necessitates dosing by injection. An alternative approach that allows oral dosing of a small molecule therapeutic agent is inhibition of dipeptidyl peptidase IV (DPP-IV), the protease primarily responsible for inactivation of endogenous GLP-1. DPP-IV inhibitors have been widely sought, and the first one to win FDA approval, sitagliptin, was the subject of a recent case study [5]. While these agents are highly successful, there is still room for improvement in the class of glucose-dependent insulin secretagogues due to the need for additional hemoglobin A1c (HbA1c) lowering beyond the 0.5–1% obtained with DPP-IV inhibitors [4] and the need for injection of peptidic GLP-1 analogs.