Sultam Hydroxamates as Novel Matrix Metalloproteinase Inhibitors

In this communication we describe the design, synthesis, and evaluation of novel sultam hydroxamates 4 as MMP-2, -9, and -13 inhibitors. Compound 26 was found to be an active inhibitor (MMP-2 IC50 = 1 nM) with 1000-fold selectivity over MMP-1 and good oral bioavailability (F = 43%) in mouse. An X-ra...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 47; no. 12; pp. 2981 - 2983
Main Authors:	Cherney, Robert J, Mo, Ruowei, Meyer, Dayton T, Hardman, Karl D, Liu, Rui-Qin, Covington, Maryanne B, Qian, Mingxin, Wasserman, Zelda R, Christ, David D, Trzaskos, James M, Newton, Robert C, Decicco, Carl P
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 03-06-2004
Subjects:	Administration, Oral Analytical, structural and metabolic biochemistry Animals Biological and medical sciences Biological Availability Crystallography, X-Ray Enzymes and enzyme inhibitors Fundamental and applied biological sciences. Psychology Hydrolases Hydroxamic Acids - chemical synthesis Hydroxamic Acids - chemistry Hydroxamic Acids - pharmacology Matrix Metalloproteinase 13 Matrix Metalloproteinase Inhibitors Medical sciences Mice Miscellaneous Models, Molecular Pharmacology. Drug treatments Structure-Activity Relationship Sulfonamides - chemical synthesis Sulfonamides - chemistry Sulfonamides - pharmacology Intravenous administration Active site Metalloendopeptidases Selectivity Modeling Pyridine derivatives Structure activity relation Six membered ring Molecular model Chemical synthesis Sulfur nitrogen heterocycle Enzyme Rodentia Benzene derivatives Oral administration Hydroxamic acid Enzyme inhibitor Inhibitor enzyme complex Bioavailability X ray diffraction In vitro Peptidases In vivo Vertebrata Mammalia Sultam Mouse Animal Hydrolases Pharmacokinetics
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Summary:	In this communication we describe the design, synthesis, and evaluation of novel sultam hydroxamates 4 as MMP-2, -9, and -13 inhibitors. Compound 26 was found to be an active inhibitor (MMP-2 IC50 = 1 nM) with 1000-fold selectivity over MMP-1 and good oral bioavailability (F = 43%) in mouse. An X-ray crystal structure of 26 in MMP-13 confirms the key hydrogen bonds and prime side binding in the active site.
Bibliography:	ark:/67375/TPS-HLDGKQCW-2 istex:70D30A234E39EA58264E244EC6E12E27156A0B42 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm049833g