Introduction of the 4-(4-bromophenyl)benzenesulfonyl group to hydrazide analogs of Ilomastat leads to potent gelatinase B (MMP-9) inhibitors with improved selectivity

Hydrazide derivatives of Ilomastat, carrying either aryl groups or distinct alkyl and arylsulfonyl moieties were synthesized and evaluated for their MMP inhibitory activity. Potent and selective MMP-9 inhibition (IC 50 = 3 nM) was observed for compound 3m (arylsulfonyl group: 4-(4-Br–C 6H 4)–C 6H 4–...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2008-09, Vol.16 (18), p.8745-8759
Hauptverfasser:	LeDour, Gwennaël, Moroy, Gautier, Rouffet, Matthieu, Bourguet, Erika, Guillaume, Dominique, Decarme, Martine, ElMourabit, Haquima, Augé, Franck, Alix, Alain J.P., Laronze, Jean-Yves, Bellon, Georges, Hornebeck, William, Sapi, Janos
Format:	Artikel
Sprache:	eng
Schlagworte:	Algorithms Benzene - chemistry Benzene - pharmacology Biological and medical sciences Hydrazines - chemical synthesis Hydrazines - pharmacology Hydroxamic Acids Ilomastat Indoles - chemical synthesis Indoles - pharmacology Inhibitory Concentration 50 Matrix metalloproteinase Matrix Metalloproteinase Inhibitors Medical sciences Miscellaneous Models, Molecular Molecular modeling Pharmacology. Drug treatments Protease Inhibitors - chemical synthesis Protease Inhibitors - pharmacology Selective MMP-9 inhibition Structure-Activity Relationship Sulfonic Acids - chemistry Sulfonic Acids - pharmacology Sulfonylhydrazide Zinc-binding group
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Zusammenfassung:	Hydrazide derivatives of Ilomastat, carrying either aryl groups or distinct alkyl and arylsulfonyl moieties were synthesized and evaluated for their MMP inhibitory activity. Potent and selective MMP-9 inhibition (IC 50 = 3 nM) was observed for compound 3m (arylsulfonyl group: 4-(4-Br–C 6H 4)–C 6H 4–SO 2–). Interaction with the S 2 enzyme subsite is mainly responsible for the inhibitory properties of this derivative as confirmed by molecular docking computation.
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2008.07.041