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

• 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
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(01)00371-7

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.