The development of new carboxylic acid-based MMP inhibitors derived from a cyclohexylglycine scaffold

A series of carboxylic acids was prepared based on cyclohexylglycine scaffolds and tested for potency as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for five enzymes within the MMP family, and a number of inhibitors such as compound 18 display low nanomolar pot...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 11; no. 15; pp. 1975 - 1979
Main Authors:	Tullis, Joshua S., Laufersweiler, Matthew J., VanRens, John C., Natchus, Michael G., Bookland, Roger G., Almstead, Neil G., Pikul, Stanislaw, De, Biswanath, Hsieh, Lily C., Janusz, Michael J., Branch, Todd M., Peng, Sean X., Jin, Yingkun Y., Hudlicky, Tomas, Oppong, Kofi
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 06-08-2001 Elsevier
Subjects:	Animals Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Carboxylic Acids - chemical synthesis Carboxylic Acids - metabolism Carboxylic Acids - pharmacology Collagenases - metabolism Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - metabolism Enzyme Inhibitors - pharmacology Glycine - analogs & derivatives Glycine - pharmacology Inhibitory Concentration 50 Matrix Metalloproteinase 1 - metabolism Matrix Metalloproteinase 13 Matrix Metalloproteinase 2 - metabolism Matrix Metalloproteinase 3 - metabolism Matrix Metalloproteinase 7 - metabolism Matrix Metalloproteinase Inhibitors Medical sciences Metalloendopeptidases - antagonists & inhibitors Metalloendopeptidases - metabolism Pharmacology. Drug treatments Protein Binding - physiology Rats Structure-Activity Relationship Stromelysin 1 Cyclohexane derivatives Sulfonamide Enzyme Enzyme inhibitor Metalloendopeptidases Selectivity In vitro Gelatinase A Peptidases α-Aminoacid Structure activity relation Hydrolases Chemical synthesis Interstitial collagenase Matrilysin
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Summary:	A series of carboxylic acids was prepared based on cyclohexylglycine scaffolds and tested for potency as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for five enzymes within the MMP family, and a number of inhibitors such as compound 18 display low nanomolar potency for MMP-2 and MMP-13, while selectively sparing MMP-1 and MMP-7. Carboxylic acids prepared from 1,3- and 1,4-cyclohexylglycine scaffolds exhibited efficacy as selective matrix metalloproteinase (MMP) inhibitors.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/S0960-894X(01)00371-7