VISIONARY PHARMACEUTICALS, INC. — Department of Health and Human Services SBIR Phase I: 300

Description

ABSTRACT Significance An epidemic proportion of Americans approximately million suffer from obesity and nonalcoholic fatty liver disease a spectrum of progressive liver disease that include steatosis non alcoholic steatohepatitis NASH fibrosis and eventually cirrhosis and hepatocellular carcinoma HCC There is no standard of care pharmacotherapy for NASH Therefore new therapeutic approaches are urgently needed IL is a critical mediator of liver fibrosis of different etiologies including NASH We have recently demonstrated that blocking of IL signaling in IL RA mice attenuated development of cholestatic and toxic liver fibrosis by suggesting that IL may serve as a novel target for anti NASH therapy Expression of IL cytokine is regulated by the nuclear receptor retinoid related orphan receptor t ROR t which belongs to a druggable class of proteins that are targeted by of prescribed drugs Hypothesis We hypothesize that a new class of ROR inverse agonists identified in our labs will most effectively attenuate the development of NASH steatohepatitis and fibrosis via inhibition of IL signaling Preliminary Data Genetic deletion of IL signaling attenuates NASH induced liver fibrosis in two mouse models of NASH the high fat diet induced and Mup uPA genetic models of NASH On the drug discovery front we identified new classes of ROR inverse agonists which based on initial medicinal chemistry studies on one series demonstrate structure activity relationships SAR potency against IL in hPBMCs IC nM oral bioavailability and effective inhibition of cholestatic and toxic fibrosis in mice Specific Aims We will prove the concept that ROR inverse agonist compounds are therapeutically efficacious in preclinical models of NASH thus justifying the effort to develop these as drugs for NASH patients Phase II SBIR Aim We will use medicinal chemistry structure based design to optimize ROR potency selectivity against other nuclear receptors and in vitro absorption distribution metabolism and excretion ADME properties of an ROR inverse agonist series Aim we will test if ROR inverse agonists from Aim have anti IL activity in primary human Peripheral Blood Lymphocytes PBLs primary human Kupffer cells Hepatic Stellate Cells and hepatocytes identified as IL target cells and use pharmacokinetic studies to select compounds with an effective pharmacological exposure in mice Aim We will test if optimized ROR inverse agonists are well tolerated in mice and are therapeutically effective in two preclinical models of NASH the fast food diet FFD and Mup uPA transgenic mice These studies will establish ROR inverse agonists as a new therapy for NASH Further the patentable and drug like leads produce herein could rapidly be translated to the clinic and developed as a targeted therapy for NASH patients Narrative An epidemic proportion of Americans approximately million suffer from obesity and nonalcoholic fatty liver disease and its progressed subtype nonalcoholic steatohepatitis NASH Liver disease causes more deaths in diabetics than cardiovascular disease yet there is no standard of care pharmacotherapy for NASH This project will develop ROR inverse agonists to block IL the key driver of disease in NASH ROR inverse agonists promise to be a targeted therapy for NASH are expected to improve outcomes for NASH patients and to have a major impact on the mortality associated with this disease