Discovery of Potent and Selective FABP4/5 Inhibitors with an Isoquinolone Scaffold as Potential Therapeutics for Inflammation-Related Diseases

Fatty acid-binding proteins 4 (FABP4) and 5 (FABP5) have emerged as promising therapeutic targets for inflammation-related diseases. Herein, we report a series of potent and selective FABP4/5 inhibitors featuring an isoquinolone scaffold through scaffold hopping of RO6806051, a dual FABP4/5 inhibitor. Among these, <b>Y18</b> was identified as the most promising compound, exhibiting potent inhibitory activity with <i>K</i>_i values of 0.41 and 2.53 μM for FABP4 and FABP5, respectively. Notably, <b>Y18</b> achieves significantly improved selectivity over FABP3 (<i>K</i>_i = 59.72 μM) compared to RO6806051, along with favorable pharmacokinetic properties, including high oral exposure and acceptable bioavailability. Oral administration of <b>Y18</b> exhibited significant anti-inflammatory effects and attenuated LPS-induced liver injury. As an anti-inflammatory compound, <b>Y18</b> demonstrates an excellent safety profile with low hERG inhibition and an LD₅₀ value greater than 2000 mg/kg. Taken together, <b>Y18</b> represents a promising dual FABP4/5 inhibitor candidate for the treatment of inflammation-related diseases.