Discovery of 3-OH-3-methylpipecolic hydroxamates: Potent orally active inhibitors of aggrecanase and MMP-13

[Display omitted] A series of 3-hydroxy-3-methylpipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was designed based on the observation of increased aggrecanase activity with substitution at the 3-position of the piperidine ring. Potency versus aggrecanase was optimized by modification of t...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 15; no. 14; pp. 3385 - 3388
Main Authors:	Noe, Mark C., Natarajan, Vijayalakshmi, Snow, Sheri L., Wolf-Gouveia, Lilli A., Mitchell, Peter G., Lopresti-Morrow, Lori, Reeves, Lisa M., Yocum, Sue A., Otterness, Ivan, Bliven, Marcia A., Carty, Thomas J., Barberia, John T., Sweeney, Francis J., Liras, Jennifer L., Vaughn, Marcie
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 15-07-2005 Elsevier
Subjects:	Administration, Oral Animals Biological and medical sciences Collagenases - metabolism Drug Design Endopeptidases - drug effects Endopeptidases - metabolism Humans Hydroxamic Acids - chemical synthesis Hydroxamic Acids - chemistry Hydroxamic Acids - pharmacokinetics Matrix Metalloproteinase 13 Matrix Metalloproteinase Inhibitors Medical sciences Miscellaneous Molecular Structure Pharmacology. Drug treatments Pipecolic Acids - chemical synthesis Pipecolic Acids - chemistry Pipecolic Acids - pharmacokinetics Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - pharmacokinetics Structure-Activity Relationship Rat Nitrogen heterocycle Metalloendopeptidases Selectivity Structure activity relation Chlorine Organic compounds Tertiary alcohol Six membered ring Piperidine derivatives Chemical synthesis Dog Fissipedia Carnivora Sulfonamide Ether Enzyme Rodentia Benzene derivatives Oral administration Hydroxamic acid Enzyme inhibitor Bioavailability In vitro Peptidases In vivo Vertebrata Mammalia Animal Hydrolases Fluorine Organic compounds Pharmacokinetics Hamster
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Summary:	[Display omitted] A series of 3-hydroxy-3-methylpipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was designed based on the observation of increased aggrecanase activity with substitution at the 3-position of the piperidine ring. Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group that binds in the S1′ pocket. These compounds also possess markedly improved bioavailability and lower metabolic clearance compared to analogous 3,3-dimethyl-5-hydroxypipecolic hydroxamates. These improvements are attributed to lowered lipophilicity proximal to the metabolically labile hydroxamic acid. Synthesis, structure activity relationships, and in vivo efficacy data are described.
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.2005.05.037