Pyran-containing sulfonamide hydroxamic acids: potent MMP inhibitors that spare MMP-1

Graphic The SAR of a series of sterically hindered sulfonamide hydroxamic acids with relatively large P 1′ groups is described. The compounds typically spare MMP-1 while being potent inhibitors of MMP-13. The metabolically more stable compounds in the series contain either a monocyclic or bicyclic p...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 14; no. 13; pp. 3389 - 3395
Main Authors:	Reiter, Lawrence A., Robinson, Ralph P., McClure, Kim F., Jones, Christopher S., Reese, Matthew R., Mitchell, Peter G., Otterness, Ivan G., Bliven, Marcia L., Liras, Jennifer, Cortina, Santo R., Donahue, Kathleen M., Eskra, James D., Griffiths, Richard J., Lame, Mary E., Lopez-Anaya, Arturo, Martinelli, Gary J., McGahee, Shunda M., Yocum, Sue A., Lopresti-Morrow, Lori L., Tobiassen, Lisa M., Vaughn-Bowser, Marcie L.
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 05-07-2004 Elsevier
Subjects:	Biological and medical sciences Collagenase Hepatocytes - drug effects Hepatocytes - metabolism Humans Hydroxamic acids Hydroxamic Acids - chemistry Matrix Metalloproteinase 1 - metabolism Matrix Metalloproteinase 13 Matrix Metalloproteinase Inhibitors Matrix Metalloproteinases - metabolism Medical sciences Miscellaneous MMP Pharmacology. Drug treatments Protease Inhibitors - chemical synthesis Protease Inhibitors - pharmacology Pyrans - chemistry Structure-Activity Relationship Sulfonamides - chemistry MMP Hydroxamic acids Collagenase Rat Toxicity Metalloendopeptidases Non peptide compound Selectivity Clearance Oxygen heterocycle Microsome Hepatocyte Structure activity relation Six membered ring Bicyclic compound Chemical synthesis Dog Interstitial collagenase Human Fissipedia Carnivora Sulfonamide Ether Enzyme Rodentia Benzene derivatives Elimination Prediction Oral administration Hydroxamic acid Enzyme inhibitor In vitro Peptidases In vivo Musculoskeletal system Vertebrata Mammalia Animal Fibrosis Hydrolases Fluorine Organic compounds Pharmacokinetics Hamster
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Summary:	Graphic The SAR of a series of sterically hindered sulfonamide hydroxamic acids with relatively large P 1′ groups is described. The compounds typically spare MMP-1 while being potent inhibitors of MMP-13. The metabolically more stable compounds in the series contain either a monocyclic or bicyclic pyran ring adjacent to the hydroxamate group. Despite the sparing of MMP-1, pre-clinical and clinical studies revealed that fibrosis in rats and MSS in humans is still produced.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2004.04.083