Rapid and efficient synthesis of a novel series of substituted aminobenzosuberone derivatives as potent, selective, non-peptidic neutral aminopeptidase inhibitors.
Racemic 5-substituted 7-aminobenzocyclohepten-6-one were synthesized and evaluated for their ability to inhibit metalloaminopeptidase activities. Unexpectedly, 5-thio substituted compounds showed enhanced inhibition potency with K(i) values in the nanomolar range against the 'one zinc' aminopeptidases from the M1 family, while most of them were rather poor inhibitors of the 'two zincs' enzymes from the M17 family. This interesting selectivity profile may guide the design of new, specific inhibitors of target mammalian aminopeptidases with one active site zinc.
Université de Haute Alsace, Laboratoire de Chimie Organique et Bioorganique, EA 4566, ENSCMu, 3, rue Alfred Werner, F-68093 Mulhouse Cedex, France. sebastien.albrecht@uha.fr
Sébastien
S
Albrecht
Emmanuel
E
Salomon
Albert
A
Defoin
Céline
C
Tarnus
D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000840:Anisoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003508:Cycloheptanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine
D000840:Anisoles; D003508:Cycloheptanes; D004791:Enzyme Inhibitors; C558240:amino-benzosuberone; D000626:Aminopeptidases