title: A library of novel hydroxamic acids targeting the metallo-protease family: design, parallel synthesis and screening.
abstract: 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.
authors.affiliation: Inserm, U761, University of Lille 2, Faculty of Pharmacy, Institut Pasteur Lille, "Biostructures and Drug Discovery" 3 rue du Pr Laguesse F-59006 Lille cedex, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Flipo
authors.forename: Terence
authors.initials: T
authors.lastname: Beghyn
authors.forename: Julie
authors.initials: J
authors.lastname: Charton
authors.forename: Virginie A
authors.initials: VA
authors.lastname: Leroux
authors.forename: Benoit P
authors.initials: BP
authors.lastname: Deprez
authors.forename: Rebecca F
authors.initials: RF
authors.lastname: Deprez-Poulain
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology; D008861:Microsomes / Q000201:enzymology; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine; D015032:Zinc / Q000737:chemistry
chemical_list: D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D000626:Aminopeptidases; D015032:Zinc