Discovery of ZG-2305, an Orally Bioavailable Factor\nInhibiting HIF Inhibitor for the Treatment of Obesity and Fatty Liver\nDisease

Genetic loss of the 2-oxoglutarate oxygenase factor inhibiting\nhypoxia-inducible factor (FIH) enhances both glycolysis and aerobic\nmetabolism. FIH is thus a potential target for adiposity control and\nimproving hepatic steatosis. We describe development of a series of\nnovel, potent, and selective FIH inhibitors that occupy both the FIH\ncatalytic site and a recently defined tyrosine conformational-flip\npocket. <b>ZG-2305</b>, with a <i>K</i><sub>i</sub> of 79.6 nM for FIH, manifests 38-fold selectivity over the hypoxia-inducible\nfactor (HIF) prolyl hydroxylase PHD2. Oral administration of <b>ZG-2305</b> in the western-diet induced obesity mouse model results\nin improved lipid accumulation and recovery from abnormal body weight/hepatic\nsteatosis. Amelioration of nonalcoholic steatohepatitis (NASH) related\npathological phenotypes in the HF-CDAA-diet induced NASH mouse model\nwas observed. Preliminary preclinical studies indicate <b>ZG-2305</b> has good pharmacokinetic properties and an acceptable safety profile.\nThe results imply <b>ZG-2305</b> is a promising candidate for\ntreatment of obesity and fatty liver disease.