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 = −13.168 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 IC 50 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 (CL int = 15.6 μl/min/mg; T 1/2 = 113.2 min) with solubility of 4.82 μM and orally bioavailable, demonstrating its potential to be used for in vivo experiments.

Biological activity of a benzene sulfonamide on perfusion pressure and coronary resistance using an isolated rat heart model

“…There several theoretical methods to determine some pharmacokinetics parameters of different dugs such as ADME/PK (Roy et al, 2022), ADME/tox (Chalkha et al, 2022) and SwissADME (Mahanthesh et al, 2020). In this study, pharmacokinetic parameters for 4-(2-Aminoethyl)benzene sulfonamide were evaluated using Admetlab 2.0 program (Azis et al, 2022;Nie et al, 2022).…”

Molecular Rearrangement of Pyrazino[2,3-c]quinolin-5(6H)-ones during Their Reaction with Isocyanic Acid

“…Hydantoin (systematically imidazolidine-2,4-dione) represents a structural motif that has been of interest to many researchers in recent years, not only chemically but also biologically [ 24 , 25 , 26 , 27 ]. Hydantoin-based compounds exhibit a broad range of biological activities, such as fungicidal, herbicidal, antitumor, anti-inflammatory, anti-HIV, hypolipidemic, antiarrhythmic, antiplatelet, and antihypertensive activities [ 28 , 29 , 30 ].…”