Structural Improvement of the Allosteric ALOX15 Inhibitor Octyl (N-(5-(1H-Indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamate

Octyl (N-(5-(1H-indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamate has previously been characterized as substrate-specific inhibitor of the linoleic acid oxygenase activity of mammalian ALOX15 orthologs. Here we aimed at optimizing the inhibitory properties of this compound by three different chemical modifications: (i) replacement of the indole core by a phenylpyrrole; (ii) introduction of hydrophilic residues into the aliphatic hydrocarbon chain of the lead compound or by replacing this building block by a triethylene glycol moiety; (iii) replacement of the sulfamoylcarbamate group by a sulfonamide. The inhibitory potencies of the modified compounds for pure rabbit ALOX15 were quantified by in vitro inhibitory assays, and our data indicate that the replacement of the rigid indole core induced a partial loss in the inhibitor’s potency. The introduction of a hydrophilic group into the aliphatic hydrocarbon chain or its replacement by a triethylene glycol moiety improved the solubility of the compound in aqueous solution, but reduced the inhibitor potency by more than one order of magnitude. Finally, the replacement of the sulfamoylcarbamate moiety by sulfonamide improved the substrate selectivity of the inhibitor for rabbit and human ALOX15. The new compounds were highly potent for human and rabbit ALOX15, but did not inhibit human ALOX15B and were less effective for mouse Alox15 (ortholog specificity).