New matrix metalloproteinase inhibitors based on γ-fluorinated α-aminocarboxylic and α-aminohydroxamic acids.

Matrix metalloproteinases (MMPs) are involved in a number of physiological as well as pathological processes such as atherosclerosis and tumorigenesis, where an up-regulation of MMPs is predominant. Fluorinated analogues of the hydroxamate-based non-peptidic broad-spectrum MMP inhibitor (MMPI) CGS 27023A were synthesized and inhibition potencies for MMP-2 and MMP-9 in the nanomolar range were measured using fluorimetric in vitro assays. The inhibition potencies of the herein reported fluorinated MMPIs were comparable or even superior in some cases to their non-fluorinated analogues. In contrast to the lead structure, both enantiomers of fluorinated MMPs were almost equally potent. Modelling studies suggest that the core α-amino hydroxamic acid residues appear to influence the relative potencies via specific inhibitor-peptidase interactions, including short fluorine-hydrogen contacts, within the enzyme's pockets. The binding of the essential hydroxamate group to the zinc ion is rather unaffected by the rest of the molecule. In contrast, the corresponding α-aminocarboxylic acid derivatives are 10(3) times less potent or were even inactive.