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

Ashis Roy (TCGLS Member), Tonmoy Sarkar (TCGLS Member), Sebak Datta (TCGLS Member), Arup Maiti (TCGLS Member), Monali Chakrabarti (TCGLS Member), Trisha Mondal (TCGLS Member), Chaitali Mondal (TCGLS Member), Apurba Banerjee (TCGLS Member), Subhasis Roy (TCGLS Member), Soumen Mukherjee (TCGLS Member), Pragati Muley (TCGLS Member), Sabyasachi Chakraborty (TCGLS Member), Manish Banerjee (TCGLS Member), Mrinalkanti Kundu (TCGLS Member), Kuldeep K. Roy
Chemical Biology and Drug Design, Volume99, Issue3 March 2022 Pages 496-503 (Published on 24th Dec 2021)

DOI : https://doi.org/10.1111/cbdd.14017

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 = −13.168 kcal/mol) of the bound ligand PAT-494 scored better than its R-enantiomer (Gscore = −9.562 kcal/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 24.6 nM in biochemical and functional assays, respectively. Further, ADME-PK studies divulged compound 1 as non-cytotoxic (19.02% cell growth inhibition at 20 μM in human embryonic kidney cells), metabolically stable against human liver microsomes (CLint = 15.6 μl/min/mg; T1/2 = 113.2 min) with solubility of 4.82 μM and orally bioavailable, demonstrating its potential to be used for in vivo experiments.