Discovery of 3,3-dimethyl-5-hydroxypipecolic hydroxamate-based inhibitors of aggrecanase and MMP-13

Noe, Mark C.; Natarajan, Vijayalakshmi; Snow, Sheri L.; Mitchell, Peter G.; Lopresti‐Morrow, Lori; Reeves, Lisa M.; Yocum, Sue A.; Carty, Thomas J.; Barberia, John A.; Sweeney, Francis J.; Liras, Jennifer; Vaughn, Marcie; Hardink, Joel R.; Hawkins, Joel M.; Tokar, Christopher J.

doi:10.1016/j.bmcl.2005.03.105

Cited by 45 publications

(23 citation statements)

References 16 publications

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“…Compound (68) ( Table 3), which exhibited the most potent aggrecanase inhibition, was selected as the lead for SAR studies at the aryl sulfonamide. As previously observed for the 3,3-dimethyl-5-hydroxypipecolic hydroxamate series, incorporation of a lipophilic ortho substituent in the benzyl or heterocyclic ether group resulted in potent aggrecanase inhibition [59]. MMP-1 inhibition proved to be also sensitive to the presence of a lipophilic ortho substituent (compare (73) and (74)).…”

Section: -Oh-3-methylpipecolic Hydroxamatesmentioning

confidence: 54%

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Progress Towards the Identification of New Aggrecanase Inhibitors

Rienzo¹,

Saxena²,

Filomia³

et al. 2009

CMC

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Degenerative diseases are still a challenging issue in clinical therapy; even though in several cases it is possible to treat symptoms, drugs able to block disease progression are lacking at present. Osteoarthritis (OA) and Rheumatoid Arthritis (RA) are degenerative diseases leading to serious cartilage destruction, affecting joint functions and giving rise to restricted movement, pain and chronic disability. Current clinical treatment for arthritis is confined to Non Steroidal Anti-Inflammatory Drugs (NSAIDs), which are effective in treating symptoms but fail to block the progression of the disease. Matrix Metalloproteases (MMPs) inhibitors have been clinically studied as possible drugs for cartilage degradation prevention. However, their clinical use has been limited by severe side-effects. Aggrecan, which plays a fundamental role in maintaining the structural and mechanical properties of cartilage, has recently been found to be specifically cleaved by "aggrecanases". Aggrecanases are multidomain zinc metalloproteases, different from MMPs, which cleave the aggrecan within the interglobular domain (IGD). Aggrecan breakdown at this site has been found to be crucial for cartilage degradation. These new findings re-addressed the interest of the research for new arthritis therapeutic agents focusing on aggrecanases rather than on MMPs. This review is meant to provide a critical appraisal of the ongoing developments of Zn-chelating and non chelating aggrecanase inhibitors, with a particular emphasis on the related structure-activity relationships (SARs), in the light of the protein structural information recently made available.

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Section: -Oh-3-methylpipecolic Hydroxamatesmentioning

confidence: 54%

“…Inhibitory potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group [59].…”

Section: 3-dimethyl-5-hydroxypipecolic Hydroxamatesmentioning

confidence: 99%

Progress Towards the Identification of New Aggrecanase Inhibitors

Rienzo¹,

Saxena²,

Filomia³

et al. 2009

CMC

View full text Add to dashboard Cite

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“…It is therefore desirable to develop inhibitors specific to the metalloproteinase of interest in order to minimise the likelihood of such effects. Whilst there have been a number of recent reports identifying derivatives selective for ADAMTS-4 or -5 over MMP-1 and -9, discrimination between these ADAMTS and MMP-2, MMP-13 or ADAM-17 is generally much less marked [92][93][94][95][96][97][98][99].…”

Section: Regulation Of Adamts Activity By Cofac-tors and Inhibitorsmentioning

confidence: 96%

ADAMTS Proteinases: Potential Therapeutic Targets?

Jones

2006

CPB

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ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteinases have been implicated in a number of connective tissue pathologies including Ehlers-Danlos syndrome type VII C, Weill-Marchesani syndrome, encephalomyelitis, and arthritis. These proteinases therefore represent potential therapeutic targets for the treatment of such conditions. The synthesis and activity of ADAMTS proteinases is regulated at multiple levels: transcription, RNA splicing, translation, proteolytic processing, cofactor stimulation and inhibition, each of which represents a possible point of therapeutic intervention. Recent research suggests that, in addition to the direct inhibition of ADAMTS proteinases with low molecular weight non-peptidic inhibitors, targeting the transcription and protein processing of these enzymes could be effective therapeutic approaches.

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“…In addition, the poor pharmacokinetic properties might attribute to the hydroxamate group, which can be easily metabolized into hydroxylamine, a known carcinogenic agent, through the cleavage of exopeptidases, leading to toxicity in long-term therapy [205]. Additionally, the C-N bond of the hydroxamate can easily change to its trans-configuration, resulting in reduced potency and/or accelerate the metabolism of the hydroxamate functionality owing to the sterical hindrance [206].…”

Section: Possible Strategies To Design Potent Mmpismentioning

confidence: 99%

An Updated Patent Therapeutic Agents Targeting MMPs

Shi¹,

Shi³

et al. 2012

PRA

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The traditional consensus that matrix metalloproteinases (MMPs) has correlation with various pathological and physiological processes led to the exploitation of a vast number of natural or synthetic broad-spectrum MMP inhibitors (MMPIs) for the prophylaxis or treatment of various MMP-related disorders, such as autoimmune, inflammatory, cardiovascular, neurodegenerative, respiratory diseases, and malignant cancer as well. Yet the unsatisfactory preclinical and/or clinical results motivated further investigation of the physiological roles of certain MMP subtypes. Despite the intricate and complicated MMP functions in normal physiology and disease pathology, the effort of designing specific inhibitors that can selectively target certain MMP family members for individualized therapy is ongoing and remains an arduous task. Success will rely on continued insight into the biological roles of these multifaced proteases. In our previous effort, we summarized various MMPIs that have entered preclinical or clinical trials as well as the patents in regard to MMPIs (Recent Pat Anticancer Drug Discov. 2010; 5(2): 109-41). In our on-going review, to illustrate the major challenges in MMP validation as druggable targets, we highlighted the physiological and pathological roles of representative MMPs, with an emphasis on description of the newly emerging MMPI-based patents, in particular, the inhibitors containing sulfonamide or sulfone motif. By analyzing the structural characteristics and selectivity profiles of these supplementary inhibitors, we hereby described their pharmaceutical application, and also expanded the strategies for potent MMPI design.

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Discovery of 3,3-dimethyl-5-hydroxypipecolic hydroxamate-based inhibitors of aggrecanase and MMP-13

Cited by 45 publications

References 16 publications

Progress Towards the Identification of New Aggrecanase Inhibitors

Progress Towards the Identification of New Aggrecanase Inhibitors

ADAMTS Proteinases: Potential Therapeutic Targets?

An Updated Patent Therapeutic Agents Targeting MMPs

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