br According to WHO estimates diabetes continues
According to WHO 2014 estimates, diabetes continues to present an increasing health risk to the global population, affecting 422 million individuals worldwide. Type 2 diabetes (T2D), which affects the vast majority (ca. 90%) of the diabetic population, occurs when the body cannot effectively utilize the insulin that is being produced. The direct effect of uncontrolled diabetes is raised blood sugar, or hyperglycemia. Over time, patients with T2D are at risk of developing other diseases, such as cardiovascular diseases, stroke, kidney failure, blindness, peripheral neuropathy, and several forms of cancer. Most of current available therapies for T2D are associated with undesirable side effects including hypoglycemia, weight gain, urinary tract infections, and gastric symptoms., Thus there is still a significant unmet medical need for new antidiabetic agents, which provide glycemic control with extended durability and improved safety. Through binding and activating several free fatty hyPerFUsion™ high-fidelity DNA polymerase receptors (FFARs), free fatty acids (FFAs) are involved in the regulation of metabolic homeostasis, and play an important role in the development of many metabolic diseases, including T2D, obesity, and atherosclerosis. GPR40, also known as FFAR1, belongs to the class A family of G-protein coupled receptors, and is expressed predominantly in pancreatic β cells and enteroendocrine cells., Activation of the GPR40 receptor by medium and long chain FFAs, leads to enhancement of insulin secretion in a glucose-dependent manner, which makes it an attractive therapeutic target to treat T2D with minimal risk of hypoglycemia and weight gain. There are numerous GPR40 partial agonists reported in the literature, several of which have been explored in clinical settings (). The most advanced compound was TAK-875 from Takeda in Phase III. Other companies such as Amgen, Eli Lilly, and Japan Tobacco had their GPR40 agonists in Phase I and Phase II clinical studies. The exact structure of JTT-851 has not been disclosed, and the structure shown in is one of the potent compounds that were disclosed in the only GPR40 patent application published by Japan Tobacco. TAK-875 is a GPR40 partial agonist that has shown clinical efficacy comparable to sulfonylureas but no propensity to cause hypoglycemia and weight gain., However, TAK-875 was terminated during Phase III trials due to drug-induced liver injury (DILI) that was presumably idiosyncratic in nature. It is proposed that the formation and accumulation of a reactive acyl glucuronide (AG) in hepatocytes. We found that the inhibition of elimination of TAK-875 and its AG by MRP2/3/4 transporters are key contributors to TAK-875-mediated DILI and thus sought to mitigate this in our series. Most of the GPR40 agonists in the literature have a carboxylic acid functional group that mimics the acid of the FFA in the binding pocket. Although there are many carboxylic acid-containing drugs that have been marketed worldwide, some of them have been withdrawn from the market due to idiosyncratic drug toxicities arising from the metabolism of the carboxylic acid moiety (e.g., AG)., Reactive AG metabolites can covalently modify endogenous proteins, which may initiate toxicity/immune responses. There are two ways to mitigate the problem: carboxylic acid-containing compounds with more stable/less reactive AG metabolites or replacing the carboxylic acid with a bioisostere. A few companies have explored the second option for non-carboxylate GPR40 agonists. For example, Astellas has identified oxadiazolidines and tetrazoles, Merck has used thiazolidine-2,4-diones, and Mochida has disclosed compounds with 1,2-thiazinan-3-one 1,1-dioxides (). Generally, these non-carboxylate GPR40 agonists are less potent than their carboxylic acid counterparts, and are still in the preclinical testing stage. Reported herein is our effort on discovery, optimization, and pharmacologic characterization of non-carboxylate GPR40 agonists with a tetrazole as the carboxylic acid bioisostere.