Comparison of the pharmacology of hydroxamate- and carboxylate-based matrix metalloproteinase inhibitors (MMPIs) for the treatment of osteoarthritis

Janusz, Michael J.; Hookfin, E.B.; Brown, Kimberly K.; Hsieh, Lily C.; Heitmeyer, S.A.; Taiwo, Yetunde O.; Natchus, Michael G.; Pikul, S.; Almstead, Neil G.; Peng, Betty; Baker, Timothy R.; Patel, Vikram S.

doi:10.1007/s00011-005-0014-4

Cited by 20 publications

(16 citation statements)

References 24 publications

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“…Compared with plasma concentrations of ALS 1-0635 (28,088 ng/ml, or 60.73 M), significantly lower concentrations have been reported for the carboxylic acid-based MMP inhibitors PGE-6292544 (ϳ5,000 ng/ ml) and PGE-2909492 (500 ng/ml) and for the hydroxamate-based MMP inhibitor PGE-3321996 (ϳ40 ng/ml) (35). Similar to the protocol used in the present study, these broad-spectrum MMP inhibitors were administered orally to rats (25 mg/kg twice daily), and plasma concentrations were measured 2 hours after the last dosing (concentrations at 2 hours posttreatment extrapolated from a graph included in the report [35]).…”

Section: Discussionmentioning

confidence: 91%

“…Interestingly, carboxylic acid-based inhibitors that exhibited good systemic exposure but were not detectable in cartilage were inactive in the MIA model, and the hydroxamic acid compound, with a cartilage concentration of 282 nM (C av ), inhibited 28% of MIAinduced cartilage degradation (35). These findings further highlight the importance of studying cartilage drug concentrations in relation to plasma exposure.…”

Section: Discussionmentioning

confidence: 91%

“…Similar to the protocol used in the present study, these broad-spectrum MMP inhibitors were administered orally to rats (25 mg/kg twice daily), and plasma concentrations were measured 2 hours after the last dosing (concentrations at 2 hours posttreatment extrapolated from a graph included in the report [35]). Interestingly, neither of the carboxylic acid-based inhibitors was detectable in cartilage, whereas the cartilage concentration of the hydroxamic acid compound was 282 nM (C av ) (35). In terms of both oral availability and exposure of target tissues, the MMP-13 inhibitors in the present study have a much better pharmacokinetic profile than the broad-spectrum inhibitors reported previously.…”

Section: Discussionmentioning

confidence: 99%

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A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

Baragi

Becher²,

Bendele³

et al. 2009

Arthritis & Rheumatism

150

127

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Objective. Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad-spectrum MMP inhibitors developed for this purpose has been restricted by dose-limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP-13 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity.Methods. Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA)-induced OA was implemented for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP-13 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP-13 inhibitors have the joint toxicity associated with broad-spectrum MMP inhibitors.Results. A number of non-hydroxamic acidcontaining compounds that showed a high degree of potency for MMP-13 and selectivity against other MMPs were designed and synthesized. Steady-state kinetics experiments and Lineweaver-Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1-0635, indicated linear, noncompeti-

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

Baragi

Becher²,

Bendele³

et al. 2009

Arthritis & Rheumatism

150

127

View full text Add to dashboard Cite

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“…The important molecular scaffold for zinc binding and the hydrophobic region lie in the 1,2,3,4-tetrahydro-isoquinoline and the aryl aromatic rings, respectively, which enhance MMP-8 hydrophobic specific binding region [134]. Several carboxylate (PGE-2909492, PGE-6292544) and hydroxamate (PGE-3321996) inhibitors have specificity for MMP-13 [135]. Other carboxylate inhibitors have less specificity for MMPs and prepared by the reaction of arylsulfonyl isocyanates with a 5-dibenzo-suberenyl/ suberyl moieties, followed by the conversion of the carboxyo-methyl to the carboxylate moieties.…”

Section: Mmp Inhibitors and Potential Benefits In Varicose Veinsmentioning

confidence: 99%

Matrix Metalloproteinases in Venous Tissue Remodeling and Varicose Vein Formation

Raffetto¹,

Khalil²

2008

CVP

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Matrix metalloproteinases (MMPs) play a major role in extracellular matrix (ECM) turnover under both physiological and pathological conditions. Studies on venous tissues from experimental animals and humans identified several MMP subtypes, and showed significant changes in the expression and activity of specific MMPs during vein wall remodeling. Also, significant research has focused on the role of MMPs in chronic venous disease (CVD) and varicose vein formation in the lower extremities and their progression to thrombophlebitis and venous leg ulcer. Several hypotheses have been forwarded regarding the pathophysiological mechanisms underlying the relation between MMPs and the formation, progression and complications of varicose veins. The effects of MMPs on ECM degradation could result in significant venous tissue remodeling and degenerative and structural changes in the vein wall, leading to venous dilation and valve dysfunction. MMPs may also induce early changes in the endothelium and venous smooth muscle function in the absence of significant ECM degradation or structural changes in the vein wall. In addition, evidence suggests increased activity of MMPs in the advanced stages of chronic venous insufficiency (CVI) associated with skin changes and leg ulceration as well as in the wound fluid environment. Several pharmacological therapies and surgical strategies are being utilized in the management of varicose veins, with variable success and recurrence rates. Inhibition of MMPs may represent a novel therapeutic intervention to limit the progression of varicose veins to CVI and leg ulceration.

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“…PGE 3321996 (hydroxamic acid based MMP inhibitor), PGE-2909492 and PGE-6292544 (carboxylic-acid based MMP inhibitors) were found to be potent MMP-2 and MMP-13 inhibitors by Janusz et al [37]. Pharmacokinetic properties of these three MMP inhibitors were also investigated in the same study.…”

Section: Application In Analysis Of Mmp Inhibitors and Their Metabolimentioning

confidence: 92%

Matrix Metalloproteinase Inhibitors: A Review on Bioanalytical Methods, Pharmacokinetics and Metabolism

Wang

Li²,

Adams³

et al. 2011

CDM

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Enzymes are major drug targets in drug discovery and development processes in the pharmaceutical and biotechnology industry. A recent survey found that nearly half of all the marketed small-molecule drugs are inhibitors of enzymes. Matrix metalloproteinases (MMPs) are a family of 28 enzymes capable of degrading the constituents of the extracellular matrix (ECM) and the basement-membrane. MMPs play an essential role in several normal physiological processes including growth, wound healing and tissue repair. Over-expression and activation of MMPs has been linked to a range of diseases which include osteoarthritis, tumor metastasis, angiogenesis and cardiovascular diseases. The development of MMP inhibitors as therapeutic agents has kept an important place in drug discovery. Therefore, there is also an increasing need for robust analytical methods for evaluation of inhibitory potency and for the analysis of MMP inhibitors and their metabolites which can even play a more significant role than the parent drug. Modern analytical techniques and hyphenated instrumentations such as liquid chromatography-mass spectrometry with a function of structure elucidation can provide a profound insight into the research of MMP inhibitors and also serve as a complementary method to zymographic techniques for the analysis of biological samples. This review mainly summarizes bioanalytical methods, pharmacokinetics and related metabolites of MMP inhibitors over the last 12 years.

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Comparison of the pharmacology of hydroxamate- and carboxylate-based matrix metalloproteinase inhibitors (MMPIs) for the treatment of osteoarthritis

Cited by 20 publications

References 24 publications

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

Matrix Metalloproteinases in Venous Tissue Remodeling and Varicose Vein Formation

Matrix Metalloproteinase Inhibitors: A Review on Bioanalytical Methods, Pharmacokinetics and Metabolism

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