Oral administration of a matrix metalloproteinase inhibitor, CGS 27023A, protects the cartilage proteoglycan matrix in a partial meniscectomy model of osteoarthritis in rabbits

O’Byrne, E. M.; Parker, David; Roberts, E. D.; Goldberg, Ronald; MacPherson, Lawrence; Blancuzzi, V.; Wilson, Douglas E.; Singh, H. N.; Ludewig, R; Ganu, Vishwas

doi:10.1007/bf01778290

Cited by 37 publications

(13 citation statements)

References 4 publications

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“…Earlier, we reported that cartilage destruction that occurs in surgical models of OA can be slowed by treatment of the animals with MMP inhibitors (31). This has been confirmed by other investigators (32).…”

Section: Discussionsupporting

confidence: 74%

Inhibition of interleukin-1?-induced cartilage oligomeric matrix protein degradation in bovine articular cartilage by matrix metalloproteinase inhibitors: Potential role for matrix metalloproteinases in the generation of cartilage oligomeric matrix protein fragments in arthritic synovial fluid

Ganu

Goldberg

Peppard

et al. 1998

Arthritis & Rheumatism

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Objective. To determine whether matrix metalloproteinases (MMPs) degrade cartilage oligomeric matrix protein (COMP) to produce fragments similar to those found in synovial fluid (SF) from patients with arthritis.Methods. COMP fragments were generated in vitro by treating (a) bovine articular cartilage with interleukin-la (IL-la), (b) purified bovine COMP with MMPs, and (c) articular cartilage with MMPs. The fragments generated in each case were analyzed by Western blot, using an antibody to the C-terminal heptadecapeptide of COMP.Results. IL-la stimulation of cartilage resulted in a fragmentation of COMP, which was inhibited by MMP inhibitors CGS 27023A and BE-94. Isolated, recombinant MMPs rapidly degraded purified COMP, as well as COMP residing in cartilage. Several COMP fragments produced in vitro had similar electrophoretic mobility to those in SF of patients with arthritis.ConcZusion. MMPs may contribute to the COMP fragments found in vivo. Quantitation of MMP-specific fragments may be useful in the evaluation of MMP inhibitors in patients with arthritis.

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Section: Discussionsupporting

confidence: 74%

Inhibition of interleukin-1?-induced cartilage oligomeric matrix protein degradation in bovine articular cartilage by matrix metalloproteinase inhibitors: Potential role for matrix metalloproteinases in the generation of cartilage oligomeric matrix protein fragments in arthritic synovial fluid

Ganu

Goldberg

Peppard

et al. 1998

Arthritis & Rheumatism

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“…[61,62] In 1995, Novartis disclosed the discovery of CGS-27023A (6; Figure 5);anon-peptidic stromelysin 1( MMP-3) inhibitor. [63,64] The compound stood out for its oral availability and blockage of cartilage matrix erosion in an in vivo rabbitm odel.Although 6 did not succeed in clinical trials, it served as atemplate structure for further development of sulfonamide-containing, second-generation hydroxamate-based inhibitors. [65,66] Analysis of the cocrystal structure of 6 within the active site of human macrophage elastase (MMP-12), as depicted in Figure 7, reveals ab inding mode in whicht he hydroxamate moiety interacts with the catalytic zinc(II) ion, as already observed for first-generationh ydroxamate-based inhibitors.…”

Section: Hydroxamate-based Zinc-binding Inhibitorsmentioning

confidence: 99%

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Fischer

Senn

Riedl

2019

Chemistry A European J

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Matrix metalloproteinases (MMPs) are involved in a multitude of severe diseases. Despite MMPs being considered druggable targets, past drug‐discovery programs have not delivered the anticipated clinical benefits. This review examines the latest structural evolution of small‐molecule inhibitors of MMPs, with a focus on the development of novel chemical entities with improved affinity and selectivity profiles. X‐ray crystallographic data of the protein targets and cocrystal structures with inhibitors proved to be key for the success achieved during this ambitious endeavor. An evolutionary view on the structural diversity generated for this class of molecules is provided. This encouraging development paves the way for the clinical utilization of this class of highly relevant therapeutic targets. The structure‐based design of superior MMP inhibitors highlights the power of this technique and displays strategies for the development of treatment options based on the modulation of challenging drug targets.

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“…The main roles of MMPs in pathology include tissue destruction, fibrosis or may be expressed as weakening of ECM. For example, destruction of tissues is observed in cancer invasion and metastasis [22], rheumatoid arthritis and osteoarthritis [23,24], formation of decubitus and various ulcers [25], periodontal disease, brain injury [26] and neuroinflammatory diseases [27]. Fibrosis of tissues is characteristic for liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis, and multiple sclerosis [28].…”

Section: Matrix Metalloproteinases (Mmps)mentioning

confidence: 99%

The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of esophageal cancer

Groblewska

Siewko

Mroczko

et al. 2012

Folia Histochem Cytobiol.

173

108

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Esophageal cancer (EC) is one of the most aggressive malignant tumors of the gastrointestinal tract. There are two distinct histological types of EC: esophageal squamous cell carcinoma and adenocarcinoma of the esophagus. Etiologic factors and the patterns of incidence of both subtypes are different. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play an important role in esophageal carcinogenesis. Gellatinases MMP-2 and MMP-9 are able to degrade collagen IV from basement membranes and extracellular matrix which is related to tumor progression, including invasion, metastasis, growth and angiogenesis. It has been shown that increased expression of MMPs plays a crucial role in the development of several human malignancies, including esophageal cancer. The activity of MMPs is regulated by their endogenous natural inhibitors (TIMPs). Among these, the roles of TIMP-1 and TIMP-2 in EC development, tumor progression and formation of metastases have been most extensively characterized and best recognized.

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Oral administration of a matrix metalloproteinase inhibitor, CGS 27023A, protects the cartilage proteoglycan matrix in a partial meniscectomy model of osteoarthritis in rabbits

Cited by 37 publications

References 4 publications

Inhibition of interleukin-1?-induced cartilage oligomeric matrix protein degradation in bovine articular cartilage by matrix metalloproteinase inhibitors: Potential role for matrix metalloproteinases in the generation of cartilage oligomeric matrix protein fragments in arthritic synovial fluid

Inhibition of interleukin-1?-induced cartilage oligomeric matrix protein degradation in bovine articular cartilage by matrix metalloproteinase inhibitors: Potential role for matrix metalloproteinases in the generation of cartilage oligomeric matrix protein fragments in arthritic synovial fluid

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of esophageal cancer

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