Structure-based discovery of (S)-2-amino-6-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione as low nanomolar, orally bioavailable autotaxin inhibitor.

Abstract

Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure-based design, synthesis, and biological investigations revealing a potent and orally bioavailable ATX inhibitor 1. During the molecular docking and scoring studies within the ATX enzyme (PDB-ID: 4ZGA), the S-enantiomer (Gscore=-13.168kcal/mol) of the bound ligand PAT-494 scored better than its R-enantiomer (Gscore=-9.562kcal/mol) which corroborated with the reported observation and analysis of the results suggested the scope of manipulation of the hydantoin substructure in PAT-494. Accordingly, the docking-based screening of a focused library of 10 compounds resulted in compound 1 as a better candidate for pharmacological studies. Compound 1 was synthesized from L-tryptophan and evaluated against ATX enzymatic activities with an IC50 of 7.6 and 24.6nM in biochemical and functional assays, respectively. Further, ADME-PK studies divulged compound 1 as non-cytotoxic (19.02% cell growth inhibition at 20μM in human embryonic kidney cells), metabolically stable against human liver microsomes (CLint =15.6μl/min/mg; T1/2 =113.2min) with solubility of 4.82μM and orally bioavailable, demonstrating its potential to be used for in vivo experiments.