New α-Substituted Succinate-Based Hydroxamic Acids as TNFα Convertase Inhibitors

Barlaam, Bernard; Bird, T. G. C.; Brempt, Christine Lambert‐van der; Campbell, David A.; Foster, Steve; Maciewicz, Rose A.

doi:10.1021/jm990377j

Cited by 94 publications

(67 citation statements)

References 41 publications

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“…In the present study, however, marimastat, a broadspectrum MMP inhibitor with the ability to block TACE activity, induced MSS (27). More experimental data regarding the role of sheddases in MSS are needed.…”

Section: Discussionmentioning

confidence: 56%

Broad‐spectrum matrix metalloproteinase inhibitor marimastat–induced musculoskeletal side effects in rats

Renkiewicz

Qiu

Lesch

et al. 2003

Arthritis & Rheumatism

168

147

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Objective. To characterize the clinical and histopathologic changes in a rat model of broad-spectrum matrix metalloproteinase (MMP)-induced musculoskeletal syndrome (MSS), and to facilitate research into the causes and treatments of MSS in humans.Methods. Male Lewis rats weighing 150-180 gm were administered 10-30 mg of the broad-spectrum MMP inhibitor marimastat over a 2-week period via surgically implanted subcutaneous osmotic pumps. The animals were monitored and scored for the onset and severity of MSS, using clinical and histologic parameters.Results. Marimastat-treated rats exhibited various clinical signs, including compromised ability to rest on their hind feet, high-stepping gait, reluctance or inability to move, and hind paw swelling. Histologically, marimastat-treated rat joints were characterized by soft tissue and bone changes, such as increased epiphyseal growth plate, synovial hyperplasia, and increased cellularity in the joint capsule and extracapsular ligaments. The severity of MSS, as judged by clinical criteria (2 blinded observers using 3 clinical parameters), paw volume, and histologic score, was nearly identical. The observed changes were indistinguishable from those reported for primate models and mimic MSS in humans.Conclusion. This simple and sensitive model of MSS is an attractive alternative for studying the pathology of MSS.

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Section: Discussionmentioning

confidence: 56%

Broad‐spectrum matrix metalloproteinase inhibitor marimastat–induced musculoskeletal side effects in rats

Renkiewicz

Qiu

Lesch

et al. 2003

Arthritis & Rheumatism

168

147

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“…BB-94, BB-1101, and GM6001 are able to broadly inhibit the MMPs; however, they have variable inhibitory effects on TACE (Barlaam et al, 1999;Skiles et al, 2004;Rosenberg et al, 2007). Additionally, in a study of lipopolysaccharide-induced inflammation in the mouse, we found differences in response to bloodbrain barrier opening between BB-1101 and BB-94 .…”

Section: Discussionmentioning

confidence: 79%

Matrix Metalloproteinase Inhibition Facilitates Cell Death in Intracerebral Hemorrhage in Mouse

Grossetete

Rosenberg

2007

J Cereb Blood Flow Metab

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Intracerebral hemorrhage (ICH) initiates an inflammatory response with secondary growth of hemorrhage and cell death. Matrix metalloproteinase (MMP) gelatinolytic activity is increased in ICH, and synthetic inhibitors to MMPs reduce edema and hemorrhage size. Recently, we found that tissue inhibitor of metalloproteinase-3 (TIMP-3) is elevated after ischemia and colocalizes with TUNEL (terminal deoxynucleotidyl transferase-mediated 2 0 -deoxyuridine 5 0 -triphosphate-biotin nick endlabeled)-labeled cells. Tissue inhibitor of metalloproteinase-3 promotes neuronal apoptosis in vitro by blocking the shedding of the tumor necrosis factor (TNF) superfamily of death receptors/ligands by stromelysin-1 (MMP-3). However, the effect of TIMP-3 and synthetic MMP inhibitors on cell death in ICH is unclear. Therefore, we used the collagenase-induced intracerebral hemorrhage (CIH) model in Timp-3 knockout and C57Bl/6 wild-type mice to study MMP expression, hemorrhage volume, and cell death. Real-time PCR showed an increase in Mmp-3 mRNA in CIH, but similar Mmp-2 and -9 mRNA expression levels in CIH and saline-injected mice. Protein levels of pro and cleaved MMP-3 were increased in CIH, and zymographic gelatinolytic activity of MMP-9 was elevated after CIH at 72 h, suggesting an exogenous source. Apoptosis was shown by increased caspase-3 levels at 2 and 72 h, and active caspase-8 by 2 and 24 h. The Timp-3 null mouse and wild types had similar hemorrhage sizes and TUNEL-labeled cells. Unexpectedly, the broad-spectrum MMP inhibitor BB-94 increased hemorrhage size and TUNEL-labeled cells. Our results fail to implicate TIMP-3 in apoptosis in CIH, but show that BB-94 increased apoptosis in CIH, possibly by blocking shedding of TNF death receptors and/or their ligands.

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“…Lithiation of the tertbutyl protected bromide (5) and subsequent reaction with triisopropyl borate afforded the boronic acid 6 which was coupled to 9-bromoanthracene under Suzuki cross-coupling conditions using Pd(Ph 3 ) 4 as catalyst and benzene-EtOH-H 2 O as solvent system to give 7 in 92% yield. Finally, deprotection of 7 to yield the corresponding thiol 8 was achieved with triflic acid and TFA in thioanisole [15].…”

Section: Synthesis Of the Ligandsmentioning

confidence: 99%

Synthesis, photophysical characterisation and metal ion binding properties of new ligands containing anthracene chromophores

Bolletta

Garelli²,

Montalti³

et al. 2004

Inorganica Chimica Acta

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Two new fluorescent chemosensors for heavy metal ions have been synthesised and their photophysical properties have been investigated. They present a pyridyl-thioether-based binding site and the anthracene moiety as a chromophore. In the experimental conditions used, no evidence is found for the formation of complexes with Pb 2þ , Zn 2þ , Cd 2þ , and Ag þ ions. On the contrary, in acetonitrile solutions both ligands strongly bind Cu 2þ and Hg 2þ cations according to a 1:1 and a 1:2 (metal:ligand) stoichiometry. In these complexes, the intense luminescence typical of anthracene derivatives is almost completely quenched and this phenomenon can be mainly attributed to an intraligand electron transfer process from the anthracene chromophore to the complexed pyridine. These results are of interest for the development of new chemosensors for the design of efficient electronic tongues for the detection of transition metal ions.

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New α-Substituted Succinate-Based Hydroxamic Acids as TNFα Convertase Inhibitors

Cited by 94 publications

References 41 publications

Broad‐spectrum matrix metalloproteinase inhibitor marimastat–induced musculoskeletal side effects in rats

Broad‐spectrum matrix metalloproteinase inhibitor marimastat–induced musculoskeletal side effects in rats

Matrix Metalloproteinase Inhibition Facilitates Cell Death in Intracerebral Hemorrhage in Mouse

Synthesis, photophysical characterisation and metal ion binding properties of new ligands containing anthracene chromophores

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