Potent, selective spiropyrrolidine pyrimidinetrione inhibitors of MMP-13

The discovery of novel, selective spirocyclic inhibitors of MMP-13 is reported. Explorations in the pyrimidinetrione series of MMP-13 inhibitors led to the discovery of a series of spiro-fused compounds that are potent and selective inhibitiors of MMP-13. While other spiro-fused motifs are hydrolyti...

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Published in:	Bioorganic & medicinal chemistry Vol. 17; no. 23; pp. 6529 - 6534
Main Authors:	Freeman-Cook, Kevin D., Reiter, Lawrence A., Noe, Mark C., Antipas, Amy S., Danley, Dennis E., Datta, Kaushik, Downs, James T., Eisenbeis, Shane, Eskra, James D., Garmene, David J., Greer, Elaine M., Griffiths, Richard J., Guzman, Roberto, Hardink, Joel R., Janat, Fouad, Jones, Christopher S., Martinelli, Gary J., Mitchell, Peter G., Laird, Ellen R., Liras, Jennifer L., Lopresti-Morrow, Lori L., Pandit, Jayvardhan, Reilly, Usa D., Robertson, Donald, Vaughn-Bowser, Marcie L., Wolf-Gouviea, Lilli A., Yocum, Sue A.
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 01-12-2007 Elsevier
Subjects:	Animals Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Collagenase-3 Enzyme Stability - drug effects Matrix metalloprotease Matrix Metalloproteinase 13 - metabolism Matrix Metalloproteinase Inhibitors Medical sciences MMP-13 Pharmacology. Drug treatments Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Pyrimidines - chemistry Pyrimidines - pharmacology Pyrimidinetrione Pyrrolidines - chemistry Pyrrolidines - pharmacology Rats Spiro Compounds - chemistry Spiro Compounds - pharmacology Structure-Activity Relationship MMP-13 Collagenase-3 Matrix metalloprotease Pyrimidinetrione Enzyme Diseases of the osteoarticular system Enzyme inhibitor Metalloendopeptidases Selectivity In vitro Spiran Pyridine derivatives Peptidases Structure activity relation Arthropathy Hydrolases Degenerative disease Fluorine Organic compounds Chemical synthesis Osteoarthritis Oxazole derivatives
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Summary:	The discovery of novel, selective spirocyclic inhibitors of MMP-13 is reported. Explorations in the pyrimidinetrione series of MMP-13 inhibitors led to the discovery of a series of spiro-fused compounds that are potent and selective inhibitiors of MMP-13. While other spiro-fused motifs are hydrolytically unstable, presumably due to electronic destabilization of the pyrimidinetrione ring, the spiropyrrolidine series does not share this liability. Greater than 100-fold selectivity versus other MMP family members was achieved by incorporation of an extended aryl–heteroaryl P1′group. When dosed as the sodium salt, these compounds displayed excellent oral absorption and pharmacokinetic properties. Despite the selectivity, a representative of this series produced fibroplasia in a 14 day rat study.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 0968-0896 1464-3405 1464-3391
DOI:	10.1016/j.bmcl.2007.09.085