Dihydroceramide Desaturase Inhibitors for Treatment of Diabetes and Other Metabolic Diseases

Despite the current FDA approved therapies the prevalence of type diabetes T D and various other metabolic diseases is reaching epidemic proportions Globally million people have overt diabetes and the prevalence of impaired fasting glucose precursor to T D referred to as pre diabetes is of the US population Consequently T D and its frequent co morbidities high triglycerides non alcoholic fatty liver disease non alcoholic steatohepatitis NAFLD NASH and cardiovascular disease increasingly account for a large proportion of global end stage renal and liver failure limb amputations blindness myocardial infarctions and strokes To address this highly unmet need Potrero Hill Therapeutics Inc PHT is discovering and developing small molecule inhibitors of dihydroceramide desaturase Des a key enzyme which catalyzes the final step in the de novo formation of ceramides molecules which drive insulin resistance high triglycerides fatty liver and atherosclerosis when produced in excess Fundamentally PHTandapos s Des inhibitor discovery effort is based upon mounting evidence in rodent disease models implicating ceramides as causal agents of high triglycerides NAFLD NASH diabetes hypertension atherosclerosis and other cardiovascular complications In this STTR Phase grant PHT will collaborate with scientists at the University of Utah College of Health to accomplish two aims which will lead to the identification of novel Des inhibitor therapeutic candidates We will synthesize and characterize the potency and drug like properties of compounds and We will further assess novel Des inhibitor activity in a liver cell assay of endogenous ceramide biosynthesis as well as their in vivo pharmacokinetic properties Ultimately successful completion of both aims will lead to novel Des inhibitor compounds which would be tested in rodent models of insulin resistance to demonstrate in vivo efficacy proof of concept Despite the current FDA approved therapies the increasing prevalence of type diabetes and various other metabolic diseases associated with insulin resistance is reaching epidemic proportions Globally million have overt diabetes and the prevalence of impaired fasting glucose precursor to type diabetes referred to as pre diabetes is of the US population Potrero Hill Therapeutics Inc is discovering and developing a novel class of therapeutics to treat diabetes abnormal blood lipids e g high triglycerides fatty liver and various other diseases associated with metabolic syndrome