Document Detail


Potent and selective 2-naphthylsulfonamide substituted hydroxamic acid inhibitors of matrix metalloproteinase-13.
MedLine Citation:
PMID:  21937229     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would provide a disease modifying therapy for the treatment of arthritis, although this goal still continues to elude the pharmaceutical industry due to issues with safety. Our efforts have resulted in the discovery of a series of hydroxamic acid inhibitors of MMP-13 that do not significantly inhibit MMP-2 (gelatinase-1). MMP-2 has been implicated in the musculoskeletal side effects resulting from pan-MMP inhibition due to findings from spontaneously occurring human MMP-2 deletions. Analysis of the SAR of hundreds of previously prepared hydroxamate based MMP inhibitors lead us to 2-naphthylsulfonamide substituted hydroxamates which exhibited modest selectivity for MMP-13 versus MMP-2. This Letter describes the lead optimization of 1 and identification of inhibitors exhibiting >100-fold selectivity for MMP-13 over MMP-2.
Authors:
Ruben A Tommasi; Sven Weiler; Leslie W McQuire; Olivier Rogel; Mark Chambers; Kirk Clark; John Doughty; James Fang; Vishwas Ganu; Jonathan Grob; Ronald Goldberg; Robert Goldstein; Stacey Lavoie; Raviraj Kulathila; William Macchia; Richard Melton; Clayton Springer; Marc Walker; Jing Zhang; Lijuan Zhu; Michael Shultz
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-8-27
Journal Detail:
Title:  Bioorganic & medicinal chemistry letters     Volume:  -     ISSN:  1464-3405     ISO Abbreviation:  -     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-9-22     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9107377     Medline TA:  Bioorg Med Chem Lett     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011 Elsevier Ltd. All rights reserved.
Affiliation:
Novartis Institutes for Biomedical Research, Inc., Cambridge, MA 02139, USA.
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