Improving potency and selectivity of a new class of non-Zn-chelating MMP-13 inhibitors

Heim-Riether, Alexander; Taylor, Steven J.; Liang, Shuang; Gao, Donghong A.; Xiong, Zhaoming; August, Elias; Collins, Brandon; Farmer, Bennett T.; Haverty, Kathleen; Hill-Drzewi, Melissa; Junker, Hans‐Dieter; Margarit, S.M.; Moss, Neil; Neumann, Thomas; Proudfoot, John; Keenan, Lana Smith; Sekul, Renate; Zhang, Qiang; Li, Jun; Farrow, Neil A.

doi:10.1016/j.bmcl.2009.07.151

Cited by 51 publications

(46 citation statements)

References 18 publications

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“…In 2009, through a Graffinity SPR microarray screening campaign, Heim-Riether et al identified hit structure 60 ( Table 7) that was subsequently determined to have an IC 50 of 430 nM against MMP-13 [111]. Compound 60 attracted their attention since it did not contain an obvious Zn-chelating group and showed selectivity over MMP-14-the one isoform postulated to play a role in MSS [112].…”

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

confidence: 97%

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

Shi²,

Tang³

et al. 2011

CMC

113

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

confidence: 97%

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

Shi²,

Tang³

et al. 2011

CMC

113

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“…7 Non zinc-chelating inhibitors have been reported for MMP-8, 85 MMP-12 [86][87][88] and MMP-13 [89][90][91][92][93][94][95][96][97][98][99] . The enthusiasm for non zinc-chelating inhibitors started with the discovery of compound 29 at Sanofi laboratories.…”

Section: Positive Impactmentioning

confidence: 99%

Targeting Matrix Metalloproteinases: Exploring the Dynamics of the S1′ Pocket in the Design of Selective, Small Molecule Inhibitors

2014

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Matrix metalloproteinases (MMPs) are important targets for pathological conditions such as arthritis, chronic obstructive pulmonary disease, and cancer. The failure of the first broad-spectrum MMP inhibitors in clinical trials has led researchers to address the selectivity as one of their main objectives. The S1' pocket has been widely used to modulate the selectivity of these enzymes because it displays the highest variability in length and shape among MMPs. In this review, we encourage medicinal chemists to also consider the dynamics of this pocket as an important parameter to achieve the desired selectivity. To support this proposal, we collect examples from the literature where the flexibility of the S1' pocket was highlighted as a relevant and significant issue affecting selectivity. We also review the experimental studies on the dynamics of this pocket.

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“…They gain their selectivity by plunging deeply into this S 1 Ј cavity and exploiting an unusual conformation of the S 1 Ј loop characterized by an additional side pocket absent in other MMPs (19). In the past few years, several other highly selective MMP-13 inhibitors with different central cores but a similar binding mode have been reported (25)(26)(27)(28)(29)(30)(31)(32). Following the same concept, the first non-zinc binding inhibitor that targets both MMP-8 and MMP-13 has been identified (compound 7) (33).…”

mentioning

confidence: 99%

Simple Pseudo-dipeptides with a P2′ Glutamate

Devel

Beau

Amoura

et al. 2012

Journal of Biological Chemistry

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Improving potency and selectivity of a new class of non-Zn-chelating MMP-13 inhibitors

Cited by 51 publications

References 18 publications

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

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

Targeting Matrix Metalloproteinases: Exploring the Dynamics of the S1′ Pocket in the Design of Selective, Small Molecule Inhibitors

Simple Pseudo-dipeptides with a P2′ Glutamate

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