Enteropeptidase (EP) is a serine protease that converts trypsinogen, which is secreted from the pancreas after a meal, into trypsin (T). Trypsin then activates protease precursors such as chymotrypsinogen, procarboxypeptidase and proelastase. The active forms of these proteases degrade dietary proteins into amino acids, which are absorbed from the small intestine. Therefore, an inhibitor of enteropeptidase and trypsin would be expected to reduce the digestion of protein and lipid, which may be an effective treatment for obesity and hyperlipidemia. Recently, the enteropeptidase and trypsin dual inhibitor SCO-792 was reported to improve insulin resistance and glucose control in a diabetic mouse model, while also showing substantial efficacy in lowering body weight in obese models. In addition, SCO-792 displayed favorable effect on improving plasma and liver lipid profiles. These findings indicate a hyperglycemic inhibitor having a serine protease inhibitory action can provide a new drug for the treatment of obesity, type II diabetes and other metabolic syndromes.<br/>Herein we report our discovery of a novel series of bicyclic triazolopyridine containing guanidinebenzoates as potent EP inhibitors. We describe an extensive medicinal chemistry campaign to identify a lead compound with potent EP inhibitory potency, desirable physical properties for gut restriction and promising <i>in vivo</i> efficacy in fecal protein excretion study in mice.

Discovery of a novel series of guanidinebenzoates as gut-restricted EP inhibitors for the treatment of metabolic syndrome

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.