Nonsteroidal FXR Ligands: Current Status and Clinical Applications.

摘要: FXR agonists have demonstrated very promising clinical results in the treatment of liver disorders such as primary biliary cirrhosis (PBC), sclerosing cholangitis (PSC), and nonalcoholic steatohepatitis (NASH). NASH, particular, is one last uncharted white territories pharma landscape, there a huge medical need large potential pharmaceutical market for NASH pharmacotherapy. Clinical efficacy superior to most other options was shown by obeticholic acid (OCA) they improved various metabolic features including steatosis well inflammation fibrosis. But OCA’s success comes with some major liabilities pruritus, high-density lipoprotein cholesterol (HDLc) lowering, low-density (LDLc) increase, drug-induced toxicity. Some these effects can be attributed on-target exerted FXR, but others it not clear whether FXR- or OCA-related. Therefore quest novel, proprietary ongoing aim increase potency selectivity over proteins overcome at least OCA-associated side through an pharmacology. In this chapter we will discuss historical efforts identification development nonsteroidal, which largely means non-bile acid-type, use.