Potent and selective 2-naphthylsulfonamide substituted hydroxamic acid inhibitors of matrix metalloproteinase-13

Tommasi, Rubén; Weiler, Sven; Mcquire, L.; Rogel, Olivier; Chambers, M.G.; Clark, Kirk; Doughty, John; Fang, James C.; Ganu, Vishwas; Grob, Jonathan E.; Goldberg, Ronald; Goldstein, Robert J.; LaVoie, Stacey; Kulathila, Raviraj; Macchia, William; Melton, Richard; Springer, Clayton; Walker, Marc; Zhang, Jing; Zhu, Lijuan; Shultz, Michael D.

doi:10.1016/j.bmcl.2011.08.087

Cited by 19 publications

(10 citation statements)

References 16 publications

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“…The replacement of the alpha isopropyl group on the amino acid moiety in 2 with an isobutyl increased both the potency against MMP‐13 (IC 50 =0.6 n m ) and the selectivity (213‐fold) over MMP‐2, but the resulting compound was more easily hydrolyzed by the enzyme than 2 . The introduction of a small substituent of hydroxy, methoxy, or ethyl at the 6‐position of the naphthalene ring in 2 led to 2‐ to 10‐fold increase in potency and only slight improvement in selectivity toward MMP‐2, which was caused the deeper penetration into the S1′ site via the naphthalene substitution …”

Section: Zinc‐binding Mmp‐13 Inhibitorsmentioning

confidence: 99%

Recent Research Advances in Selective Matrix Metalloproteinase‐13 Inhibitors as Anti‐Osteoarthritis Agents

2017

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Matrix metalloproteinase-13 (MMP-13) plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). The subtle differences between the S1' loop of MMP-13 and that of other MMPs offer a structural base for the design of selective MMP-13 inhibitors to mitigate the unperceived risk associated with inhibiting other MMP isoforms. In this review, we summarize zinc-binding and non-zinc-binding selective MMP-13 inhibitors. The zinc-binding MMP-13 inhibitors contain a small set of zinc-binding groups (ZBGs), including hydroxamic acid, pyrimidinetrione, reversed hydroxamic acid and hydantoin, carboxylic acid, 1,2,4,-triazole, and 1,2,4,-triazolone. The non-zinc-binding MMP-13 inhibitors have different structural scaffolds, including diphenyl ethers, biaryls (aryltetrazoliums, arylfurans, pyrazole-indoles), pyrimidines, and aryl/cycloalkyl-fused pyrimidines. This review provides a systematic overview of recent developments in MMP-13 inhibitors for the treatment of OA, with emphasis on their enzyme inhibitory potency, selectivity, and biological activities, and highlights the various binding modes of typical inhibitors with MMP-13.

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Section: Zinc‐binding Mmp‐13 Inhibitorsmentioning

confidence: 99%

Recent Research Advances in Selective Matrix Metalloproteinase‐13 Inhibitors as Anti‐Osteoarthritis Agents

2017

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“…39-41 However, early generations of these compounds suffered from rapid oxidation of the thiol group, resulting in a reduced ability of these compounds to coordinate the active site Zn 2+ due to disulfide formation. 32 In order to assess the stability of these new compounds, studies were performed to evaluate the thiol’s zinc chelation over time.…”

Section: Resultsmentioning

confidence: 99%

Matrix Metalloproteinase Inhibitors Based on the 3-Mercaptopyrrolidine Core

et al. 2013

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New series of pyrrolidine mercaptosulfide, 2-mercaptocyclopentane arylsulfonamide, and 3-mercapto-4-arylsulfonamido pyrrolidine matrix metalloproteinase inhibitors (MMPIs) were designed, synthesized, and evaluated. Exhibiting unique properties over other MMPIs (e.g., hydroxamates), these newly reported compounds are capable of modulating activities of several MMPs in the low nanomolar range, including MMP-2 (~2 to 50 nM), MMP-13 (~2 to 50 nM), and MMP-14 (~4 to 60 nM). Additionally these compounds are selective to intermediate- and deep-pocket MMPs but not shallow-pocketed MMPs (e.g., MMP-1, ~850 to >50,000 nM; MMP-7, ~4,000 to >25,000 nM). Our previous work with the mercaptosulfide functionality attached to both cyclopentane and pyrrolidine frameworks demonstrated that the cis-(3S,4R)-stereochemistry was optimal for all of the MMPs tested. However, in our newest compounds an interesting shift of preference to the trans-form of the mercaptosulfonamides was observed with increased oxidative stability and biological compatibility. We also report several kinetic and biological characteristics showing that these compounds may be used to probe the mechanistic activities of MMPs in disease.

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“…MMP-2 has been implicated in the musculoskeletal side effects resulting from pan-MMP inhibition due to findings from spontaneously occurring human MMP-2 deletions. [30]…”

Section: Hydroxamic Acid As Mutagenic and Mmp (Matrix Metalloproteinamentioning

confidence: 99%

Hydroxamic acid - A novel molecule for anticancer therapy

Pal¹,

Saha²

2012

J Adv Pharm Technol Res

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Hydroxamic acid is a potent moiety not only in the field of cancer therapy but also as a mutagenic agent. Among the various derivatives of hydroxamic acid, SAHA (Suberoylanilide Hydroxamic Acid) is considered as a potent anticancer agent. Scientists from the different corner synthesized different hydroxamic acid moieties with some straight chain oxazole, thiadiazole, biphenyl moieties in the terminal position. Acetylation and deacetylation of histones of the core proteins of nucleosomes in chromatin play an important role in the regulation of gene expression. The level of acetylation of histones is established and maintained by two classes of enzymes, histone acetyltransferase and histone deacetylases, which have been identified as transcriptional coactivators and transcriptional corepressors, respectively. There is increasing evidence that aberrant histone acetylation has been linked to various malignant diseases. Great efforts are currently underway for the design of more potent and less toxic candidates for the treatment of cancer. In recent years, hydroxamic acid derivatives have attracted increasing attention for their potential as highly efficacious in combating various etiological factors associated with cancer. Our main intention to draw an attention is that this single functional moiety has not only fit in the receptor but also create a diversified activity.

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Potent and selective 2-naphthylsulfonamide substituted hydroxamic acid inhibitors of matrix metalloproteinase-13

Cited by 19 publications

References 16 publications

Recent Research Advances in Selective Matrix Metalloproteinase‐13 Inhibitors as Anti‐Osteoarthritis Agents

Recent Research Advances in Selective Matrix Metalloproteinase‐13 Inhibitors as Anti‐Osteoarthritis Agents

Matrix Metalloproteinase Inhibitors Based on the 3-Mercaptopyrrolidine Core

Hydroxamic acid - A novel molecule for anticancer therapy

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