Structure-based linker exploration: Discovery of 1-ethyl-1H-indole analogs as novel ATX inhibitors

[Display omitted] •32 indole analogs bearing acyl hydrazone or urea linkers as potent ATX inhibitors.•The amide bond reverse strategy was involved in the exploration of the linker moiety.•Structure based optimization furnished the most powerful inhibitor 24 (2.3 nM).•The binding mode of 24 with ATX ideally elucidated its excellent enzymatic potency. Aiming to develop novel ATX inhibitors, an indole-3-carboxylic acid lead Indole-1 was identified through high-throughput screening (HTS) efforts. The Indole-1 analogs 1–7 was firstly prepared which exerted mild activity comparable to Indole-1 (740 nM) in ATX enzyme assay. Further structural modification to identify type IV ATX inhibitors was proceeded through derivatization of the indole-3-carboxylic acid group. Resultantly, compounds 8–17 containing acyl hydrazone linker displayed poor activity (over 3.49 μM). Alternatively, replacing the acylhydrazone linker with urea counterpart by the amide bond reversal principle, the acquired compounds 18–22 achieved obvious improvements with submicromolar activities. Furthermore, with the aim to reducing cLogP, the thiazole ring of 18–22 was altered to the benzamide (23–32) with the urea linker unchanged. Remarkably, the benzamide derivative 24 with 4-hydroxy piperidine fragment was identified which exhibited prominent activity with IC50 value of 2.3 nM. Especially, dedicated molecular docking study was throughout the modification process which qualified 24 as optimal entity in accordance with the ATX inhibitory results.