Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis

Schnute, Mark E.; O’Brien, Patrick; Nahra, Joe; Morris, Margaret E.; Roark, W. H.; Hanau, Cathleen E.; Ruminski, Peter; Scholten, Jeffrey D.; Fletcher, Theresa; Hamper, Bruce C.; Carroll, Jeffery N.; Patt, William C.; Shieh, Huey‐Sheng; Collins, Brandon; Pavlovsky, A.G.; Palmquist, Katherine E.; Aston, Karl; Hitchcock, Jeffrey; Rogers, Michael L.; McDonald, Joseph J.; Johnson, Adam R.; Munie, Grace E.; Wittwer, Arthur J.; Man, Chiu-Fai; Settle, Steven L.; Nemirovskiy, Olga V.; Vickery, Lillian; Agawal, Arun; Dyer, Richard D.; Sunyer, Teresa

doi:10.1016/j.bmcl.2009.11.081

Cited by 46 publications

(40 citation statements)

References 26 publications

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“…Full-length recombinant human proteins were used for MMPs 1, 2, 9, and 13. The catalytic domain of the protein was used for MMPs 3,7,8,10,12,14,15,16,20,24,25, and 26. PF152 potency was also evaluated using full-length bovine type II collagen by quantifying the generation of the one-quarter-length and threequarter-length fragments upon digestion with full-length human MMP-13 using sodium dodecyl sulfate-polyacrylamide gel electrophoresis.…”

Section: Methodsmentioning

confidence: 99%

Cartilage degradation biomarkers predict efficacy of a novel, highly selective matrix metalloproteinase 13 inhibitor in a dog model of osteoarthritis: Confirmation by multivariate analysis that modulation of type ii collagen and aggrecan degradation peptides parallels pathologic changes

Settle¹,

Vickery²,

Nemirovskiy³

et al. 2010

Arthritis & Rheumatism

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Objective. To demonstrate that the novel highly selective matrix metalloproteinase 13 (MMP-13) inhibitor PF152 reduces joint lesions in adult dogs with osteoarthritis (OA) and decreases biomarkers of cartilage degradation.Methods. The potency and selectivity of PF152 were evaluated in vitro using 16 MMPs, TACE, and ADAMTS-4 and ADAMTS-5, as well as ex vivo in human cartilage explants. In vivo effects were evaluated at 3 concentrations in mature beagles with partial medial meniscectomy. Gross and histologic changes in the femorotibial joints were evaluated using various measures of cartilage degeneration. Biomarkers of cartilage turnover were examined in serum, urine, or synovial fluid. Results were analyzed individually and in combination using multivariate analysis.Results. The potent and selective MMP-13 inhibitor PF152 decreased human cartilage degradation ex vivo in a dose-dependent manner. PF152 treatment of dogs with OA reduced cartilage lesions and decreased biomarkers of type II collagen (type II collagen neoepitope) and aggrecan (peptides ending in ARGN or AGEG) degradation. The dose required for significant inhibition varied with the measure used, but multivariate analysis of 6 gross and histologic measures indicated that all doses differed significantly from vehicle but not from each other. Combined analysis of cartilage degradation markers showed similar results.Conclusion. This highly selective MMP-13 inhibitor exhibits chondroprotective effects in mature animals. Biomarkers of cartilage degradation, when evaluated in combination, parallel the joint structural changes induced by the MMP-13 inhibitor. These data support the potential therapeutic value of selective MMP-13 inhibitors and the use of a set of appropriate biomarkers to predict efficacy in OA clinical trials.Osteoarthritis (OA) is a chronic degenerative joint disease affecting primarily aged or injured joints. The disease is characterized by an imbalance between cartilage synthesis and degradation, with increased breakdown of matrix components leading to proteoglycan loss and cartilage fibrillation, eventually resulting in severe cartilage defects. These changes are irreversible, and the only treatment other than palliative symptom control is total joint replacement. Therefore, the discovery of a disease-modifying osteoarthritis drug (DMOAD) would fill a large unmet medical need.

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Section: Methodsmentioning

confidence: 99%

Cartilage degradation biomarkers predict efficacy of a novel, highly selective matrix metalloproteinase 13 inhibitor in a dog model of osteoarthritis: Confirmation by multivariate analysis that modulation of type ii collagen and aggrecan degradation peptides parallels pathologic changes

Settle¹,

Vickery²,

Nemirovskiy³

et al. 2010

Arthritis & Rheumatism

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“…[130] Schnute et al synthesized inhibitor 32 (Figure20), in which at etrazole ring was implementeda sa ni sostericr eplacement for an amide. [131] This alteration improved the inhibitory activity of 32 against full-length MMP-13,b ut did not improve the addressed CACO-2p ermeability (in vitro model for the estimation of the bioavailability of drug candidates by measuring the permeability through human small intestine mucosa) of the ligand.F urther modifications, such as the change from an aromatic ring within the hydrophobic S1' selectivity loop, distal to the catalytic center,t oatrans-cyclohexyl carboxylic acid moiety,resulted in as eries of compounds with elevated potency againstM MP-13. The stereochemistry at the cyclohexyl ring provedi mportant because the cis isomer turned out to be significantly less potent than the trans analogue, with K i values against full-length MMP-13 of 59.2 and 4.4 nm,r espectively.…”

Section: Non-zinc-binding Inhibitorsmentioning

confidence: 98%

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 discovery of compound 62 offered the opportunity to merge activity-based learnings from these series with a simplified core ring template that could provide improved physiochemical properties. So in 2010, Schnute et al described the optimization of the monocyclic hit 62 to provide highly potent, selective, and orally-bioavailable MMP-13 inhibitors 63 ( Table 7) that demonstrated cartilage protection in preclinical OA animal models [113]. Compound 63-1 demonstrated potent inhibition of full length MMP-13 (Ki = 4.4 nM) and exhibited exquisite selectivity (Ki >25 μM) against a set of 13 MMP enzymes, TACE, ADAMTS-4, and ADAMTS-5.…”

Section: Non-zinc-chelating-based Mmp-13 Inhibitorsmentioning

confidence: 98%

New Hope for the Treatment of Osteoarthritis Through Selective Inhibition of MMP-13

Shi²,

Tang³

et al. 2011

CMC

112

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Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage that eventually leads to a complex process involving degradation of various components of the cartilage matrix, chief among them are the cartilage-specific type II collagen (CII) and aggrecan. While the loss of aggrecan is thought to be an early and reversible process, degradation of CII is considered to be irreversible and a key step in the loss of structural and functional integrity of cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. It is the major collagenase in OA cartilage and has the highest activity against CII. However, the clinical utility of broad-spectrum MMP inhibitors developed for treatment of OA has been restricted by dose- and duration-dependent musculoskeletal side effects in humans. Consequently, selectively inhibiting the MMP-13 would seem to be an attractive therapeutic objective. This review mainly focuses on selective MMP-13 inhibitors development in terms of OA since the late 90s, in terms of synthetic compounds of low molecular mass incorporating specific zinc-binding groups, non-zinc-binding groups. In addition, dual inhibitors of MMP-13 and aggrecanase are also reviewed. Special emphasis is placed on logistic concerns for lead compound search as well as the structure-activity relationship (SAR) in this field. Through these methods, new hope is emerging for the treatment of OA through selective inhibition of MMP-13.

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Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis

Cited by 46 publications

References 26 publications

Cartilage degradation biomarkers predict efficacy of a novel, highly selective matrix metalloproteinase 13 inhibitor in a dog model of osteoarthritis: Confirmation by multivariate analysis that modulation of type ii collagen and aggrecan degradation peptides parallels pathologic changes

Cartilage degradation biomarkers predict efficacy of a novel, highly selective matrix metalloproteinase 13 inhibitor in a dog model of osteoarthritis: Confirmation by multivariate analysis that modulation of type ii collagen and aggrecan degradation peptides parallels pathologic changes

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

New Hope for the Treatment of Osteoarthritis Through Selective Inhibition of MMP-13

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