Discovery of 3,3-dimethyl-5-hydroxypipecolic hydroxamate-based inhibitors of aggrecanase and MMP-13

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 11; pp. 2808 - 2811
• Main Authors: Noe, Mark C., Natarajan, Vijayalakshmi, Snow, Sheri L., Mitchell, Peter G., Lopresti-Morrow, Lori, Reeves, Lisa M., Yocum, Sue A., Carty, Thomas J., Barberia, John A., Sweeney, Francis J., Liras, Jennifer L., Vaughn, Marcie, Hardink, Joel R., Hawkins, Joel M., Tokar, Christopher
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 02-06-2005; Elsevier
• Subjects: Biological and medical sciences; Endopeptidases - drug effects; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Matrix Metalloproteinase 13; Matrix Metalloproteinase Inhibitors; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Sulfonamide; Enzyme; Nitrogen heterocycle; Benzene derivatives; Hydroxamic acid; Metalloendopeptidases; Selectivity; In vitro; Peptidases; Structure activity relation; Chlorine Organic compounds; Piperidine derivatives; Hydrolases; Chemical synthesis; Interstitial collagenase
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.03.105

A series of pipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was discovered based on screening known inhibitors of TNF-α converting enzyme (TACE). Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group. Incorporation of geminal alkyl substitution at the 3-position of the piperidine ring improved metabolic stability, presumably by increasing steric hindrance around the metabolically labile hydroxamic acid. This modification also resulted in dramatic improvement of aggrecanase activity with a slight reduction in selectivity versus MMP-1. Synthesis, structure activity relationships, and strategies to reduce metabolic clearance are described.
A series of pipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was discovered based on screening known inhibitors of TNF-α converting enzyme (TACE). Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group. Incorporation of geminal alkyl substitution at the 3-position of the piperidine ring improved metabolic stability, presumably by increasing steric hindrance around the metabolically labile hydroxamic acid. This modification also resulted in dramatic improvement of aggrecanase activity with a slight reduction in selectivity versus MMP-1. Synthesis, structure activity relationships, and strategies to reduce metabolic clearance are described.