Potent and Selective Carboxylic Acid-Based Inhibitors of Matrix Metalloproteinases

• Published in: Journal of medicinal chemistry Vol. 44; no. 16; pp. 2499 - 2502
• Main Authors: Pikul, Stanislaw, Ohler, Norman E, Ciszewski, Greg, Laufersweiler, Michael C, Almstead, Neil G, De, Biswanath, Natchus, Michael G, Hsieh, Lily C, Janusz, Michael J, Peng, Sean X, Branch, Todd M, King, Selane L, Taiwo, Yetunde O, Mieling, Glen E
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 02-08-2001
• Subjects: Biological and medical sciences; Biphenyl Compounds - chemical synthesis; Biphenyl Compounds - chemistry; Blood Proteins - chemistry; Carboxylic Acids - chemical synthesis; Carboxylic Acids - chemistry; Matrix Metalloproteinase Inhibitors; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Solubility; Stereoisomerism; Structure-Activity Relationship; Sulfonamide; Enzyme; Benzene derivatives; Solubility; Enzyme inhibitor; Metalloendopeptidases; Selectivity; Serum protein; Organic carbamate; In vitro; Peptidases; α-Aminoacid; Biological fixation; Structure activity relation; Piperidine derivatives; Hydrolases; Chemical synthesis; Blood serum
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm015531s

A novel series of carboxylic acids containing a substituted piperidine were synthesized and tested for inhibition of selected matrix metalloproteinases. Multiple analogues prepared based on this novel design were found to inhibit the target MMPs (MMP-2, -3, -8, -9, and -13) with unprecedented, low nanomolar potency while, at the same time, sparing MMP-1 and MMP-7. Solubility and plasma protein binding of several members of this new series of carboxylic acids were also investigated.