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, Y18 was identified
as the most promising compound, exhibiting potent inhibitory activity
with Ki values of 0.41 and 2.53 μM
for FABP4 and FABP5, respectively. Notably, Y18 achieves
significantly improved selectivity over FABP3 (Ki = 59.72 μM) compared to RO6806051, along with favorable
pharmacokinetic properties, including high oral exposure and acceptable
bioavailability. Oral administration of Y18 exhibited
significant anti-inflammatory effects and attenuated LPS-induced liver
injury. As an anti-inflammatory compound, Y18 demonstrates
an excellent safety profile with low hERG inhibition and an LD50 value greater than 2000 mg/kg. Taken together, Y18 represents a promising dual FABP4/5 inhibitor candidate for the
treatment of inflammation-related diseases.