A library of novel hydroxamic acids targeting the metallo-protease family: Design, parallel synthesis and screening

We report here the design and parallel synthesis of 217 compounds based on a malonic–hydroxamic acid template. These compounds are obtained via a two-step solution-phase procedure. The set of diverse building-blocks used makes this strategy suitable for the search of inhibitors of various metallo-pr...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2007, Vol.15 (1), p.63-76
Hauptverfasser:	Flipo, Marion, Beghyn, Terence, Charton, Julie, Leroux, Virginie A., Deprez, Benoit P., Deprez-Poulain, Rebecca F.
Format:	Artikel
Sprache:	eng
Schlagworte:	Aminopeptidases Aminopeptidases - antagonists & inhibitors Aminopeptidases - chemistry Animals Chemical biology Combinatorial Chemistry Techniques Combinatorial Chemistry Techniques - methods Drug Design Drug Evaluation, Preclinical Enzyme Activation Enzyme Activation - drug effects Hydroxamate Hydroxamic Acids Hydroxamic Acids - chemical synthesis Hydroxamic Acids - chemistry Hydroxamic Acids - pharmacology Kidney Kidney - enzymology Life Sciences Malonic Metallo-protease inhibitors Microsomes Microsomes - enzymology Molecular Structure Pharmaceutical sciences Protease Inhibitors Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Stereoisomerism Structure-Activity Relationship Swine Targeted library Zinc Zinc - chemistry Zn 2+ binding group
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Zusammenfassung:	We report here the design and parallel synthesis of 217 compounds based on a malonic–hydroxamic acid template. These compounds are obtained via a two-step solution-phase procedure. The set of diverse building-blocks used makes this strategy suitable for the search of inhibitors of various metallo-proteases and for the investigation of the biological role of new metallo-proteases. As a proof of concept, we screened this library on Neutral Aminopeptidase (APN; EC 3.4.11.2), the prototypal enzyme of the M1 family. Several submicromolar inhibitors were identified.
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2006.10.010