2005
DOI: 10.1021/jm051101g
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Selective Inhibition of Matrix Metalloproteinase Isozymes and in Vivo Protection against Emphysema by Substituted γ-Keto Carboxylic Acids

Abstract: The synthesis and matrix metalloproteinase (MMP) inhibitory activity of a series of gamma-keto carboxylic acids are described. Among nine MMP isozymes tested, compound 1j displays selective inhibition of MMP-2, -9, and -12 with IC(50) values between 0.20 and 1.51 microuM, and in male golden Syrian hamsters, it shows protection against PPE-induced emphysema.

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Cited by 24 publications
(11 citation statements)
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“…In an animal model of emphysema and in patients with COPD, several MMPs, including MMP-9, are elevated in sputum, BALF, and lung tissue specimens [2, 30, 44, 45] and are related to poor lung function. MMP inhibition attenuates emphysema and small-airway remodeling in guinea pigs and hamsters [46, 47]. However, D’Armiento et al .…”
Section: Discussionmentioning
confidence: 99%
“…In an animal model of emphysema and in patients with COPD, several MMPs, including MMP-9, are elevated in sputum, BALF, and lung tissue specimens [2, 30, 44, 45] and are related to poor lung function. MMP inhibition attenuates emphysema and small-airway remodeling in guinea pigs and hamsters [46, 47]. However, D’Armiento et al .…”
Section: Discussionmentioning
confidence: 99%
“…MMPs are considered to be crucial for tissular remodeling processes in most organs, including the lung, and a role of MMPs in the development of pulmonary emphysema has been suspected. A gain-of-function polymorphism in the promoter of MMP-9 is linked to the occurrence of pulmonary emphysema in humans (9), and the pharmacological inhibition of MMPs protects against emphysema in hamsters exposed to elastase (15). It was therefore interesting that while an elevation in MMP-2 and MMP-9 activity was initially detected at similar levels in BALF of mice early after elastase instillation (6th hour and day 1), MMP activation resolved much faster in KGF-treated mice.…”
Section: Discussionmentioning
confidence: 99%
“…By optimization of the benzoxazole substitution, selective MMP-13 (exemplified by 857081-53-9) [105] and aggrecanase ADAMTS [106] nM inhibitors were made. The γ -ketocarboxylate (second structure of this figure) is an MMP-2, -9 and -12 selective inhibitor (although only with μM potency) with efficacy in a hamster PPE-induced emphysema model [107].…”
Section: New Generation Hydroxamate-based Mmp Inhibitorsmentioning
confidence: 99%