David Hollenback, Eva Hambruch, Gero Fink, Manfred Birkel, Andreas Schulz, Martin Hornberger, Kathy Liu, Kelly MacLennan Staiger, Helen Desiree Krol, Ulrich Deuschle, Christoph Steeneck, Olaf Kinzel, John T Liles, Grant Budas, William J Watkins, Claus Kremoser
The farnesoid X receptor (FXR) is a nuclear receptor that controls bile acid, lipid, and cholesterol metabolism. FXR-targeted drugs have shown promise in late-stage clinical trials for non-alcoholic steatohepatitis. Herein, we used clinical results from our first non-steroidal FXR agonist, Px-102 (4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl] benzoic acid), to develop cilofexor, a potent, non-steroidal FXR agonist with a more manageable safety profile. Px-102 demonstrated the anticipated pharmacodynamic (PD) effects in healthy volunteers but caused a 2-fold increase in alanine aminotransferase (ALT) activity and changes in cholesterol levels...
February 26, 2024: Journal of Pharmacology and Experimental Therapeutics