α,β-Cyclic-β-benzamido hydroxamic acids: Novel templates for the design, synthesis, and evaluation of selective inhibitors of TNF-α converting enzyme (TACE)

Ott, Gregory R.; Asakawa, Naoyuki; Lu, Zhonghui; Liu, Rui‐Qin; Covington, Maryanne; Vaddi, Krishna; Qian, Mingxin; Newton, Robert; Christ, David D.; Traskos, James M.; Decicco, Carl P.; Duan, James J.‐W.

doi:10.1016/j.bmcl.2007.11.059

Cited by 36 publications

(23 citation statements)

References 31 publications

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“…A total of 443 TACE inhibitors used in this work were collected from recently published papers [15,[18][19][20][21][23][24][25][26][27][29][30][31][32][33][34][35][36][37][38][39][40][41]. The majority of the tested inhibitors are efficient TACE inhibiting agents showing IC 50 value from 0.000066 mM to 100 mM.…”

Section: Data Setsmentioning

confidence: 99%

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Prediction of novel and selective TNF-alpha converting enzyme (TACE) inhibitors and characterization of correlative molecular descriptors by machine learning approaches

Yang

et al. 2009

Journal of Molecular Graphics and Modelling

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Section: Data Setsmentioning

confidence: 99%

“…So some dual TACE and MMP-13 inhibitors which do not inhibit MMP-1 were developed [36]. In addition to these TACE inhibitors, there remain lots of new TACE inhibitors designed by other strategies [37][38][39][40][41]. These TACE inhibitors from different chemical classes have different interactions with TACE.…”

Section: Introductionmentioning

confidence: 98%

Prediction of novel and selective TNF-alpha converting enzyme (TACE) inhibitors and characterization of correlative molecular descriptors by machine learning approaches

Yang

et al. 2009

Journal of Molecular Graphics and Modelling

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“…On the basis of structural variations and differences in the biological activity, ultimately 80 compounds (Fig. 1, Table 1) with IC 50 values ranging from 0.066 to 17,000 nM were used in the study [18][19][20][21][22][23][24][25][26][27][28][29]. The IC 50 values (in moles/litre) was converted into negative logarithm of IC 50 (pIC 50 ).…”

Section: Data Setmentioning

confidence: 99%

“…A set of 486 molecules having TACE inhibitory activity was collected from the literature [18][19][20][21][22][23][24][25][26][27][28][29]. Compounds with defined stereochemistry and well defined biological activity only were selected, excluding the recemates and those compounds which were reported to have biological activity less than or more than a particular value.…”

Section: Data Setmentioning

confidence: 99%

Development of predictive pharmacophore model for in silico screening, and 3D QSAR CoMFA and CoMSIA studies for lead optimization, for designing of potent tumor necrosis factor alpha converting enzyme inhibitors

Murumkar

Zambre

Yadav

2010

J Comput Aided Mol Des

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A chemical feature-based pharmacophore model was developed for Tumor Necrosis Factor-alpha converting enzyme (TACE) inhibitors. A five point pharmacophore model having two hydrogen bond acceptors (A), one hydrogen bond donor (D) and two aromatic rings (R) with discrete geometries as pharmacophoric features was developed. The pharmacophore model so generated was then utilized for in silico screening of a database. The pharmacophore model so developed was validated by using four compounds having proven TACE inhibitory activity which were grafted into the database. These compounds mapped well onto the five listed pharmacophoric features. This validated pharmacophore model was also used for alignment of molecules in CoMFA and CoMSIA analysis. The contour maps of the CoMFA/CoMSIA models were utilized to provide structural insight for activity improvement of potential novel TACE inhibitors. The pharmacophore model so developed could be used for in silico screening of any commercial/in house database for identification of TACE inhibiting lead compounds, and the leads so identified could be optimized using the developed CoMSIA model. The present work highlights the tremendous potential of the two mutually complementary ligand-based drug designing techniques (i.e. pharmacophore mapping and 3D-QSAR analysis) using TACE inhibitors as prototype biologically active molecules.

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“…In 2008, Ott et al at Bristol-Myers Squibb reported the synthesis and evaluation of novel TACE inhibitors 43 ( Table 2) based upon cis-, -cyclic--benzamido hydroxamic acid 42, with focus on five-membered ring motifs including substituted (1R,2S)cyclo-pentyl, (3S,4S)-pyrrolidinyl and (3R,4S)-tetrahydrofuranyl scaffolds [89]. Prior experience suggested that increasing the polarity of the molecule would drive potency into the desired range (IC 50 < 200 nM).…”

Section: Hydroxamic Acid-based Tace Inhibitors Bearing a 4-(2quinolinmentioning

confidence: 99%

Discovery of Selective Small Molecular TACE Inhibitors for the Treatment of Rheumatoid Arthritis

Shi²,

Tang³

et al. 2012

CMC

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Rheumatoid arthritis (RA) is a chronic, inflammatory disease that afflicts 1-2% of the world population, characterized by an immune mediated inflammatory synovitis that leads to joint destruction, functional impairment, and reduced quality of life. The treatment goals of RA should be longterm substantial relief of pain, arrested joint inflammation and damage, and improved function. Current treatment can be divided into four classes, namely general analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, disease modifying anti-rheumatic drugs (DMARDs) and biological agents (tumor-necrosis factor modifiers). However, gastrointestinal (GI) side effects of NSAIDs cannot be neglected, direct joint injections of glucocorticoids cannot be injected more than once every 3 months, synthetic DMARDs is far from optimal and only minority of patients achieved longterm remission, the biologics are very expensive to manufacture, need to be injected, and can cause allergic reactions. An alternative and good approach to the treatment of this disease is to lower the levels of tumour necrosis factor-α (TNF-α) in RA, which can be achieved by selectively inhibiting the tumour necrosis factor-α converting enzyme (TACE) that generate these cytokines using cheaper small molecules. This review focuses on the current status of selective small molecule inhibitors of TACE, with respect to lead compound search, inhibitors design approach, structure-activity relationship (SAR) and pharmacological studies in animals and humans. Through these methods, new hope is emerging for the treatment of RA through selective inhibition of TACE.

show abstract

α,β-Cyclic-β-benzamido hydroxamic acids: Novel templates for the design, synthesis, and evaluation of selective inhibitors of TNF-α converting enzyme (TACE)

Cited by 36 publications

References 31 publications

Prediction of novel and selective TNF-alpha converting enzyme (TACE) inhibitors and characterization of correlative molecular descriptors by machine learning approaches

Prediction of novel and selective TNF-alpha converting enzyme (TACE) inhibitors and characterization of correlative molecular descriptors by machine learning approaches

Development of predictive pharmacophore model for in silico screening, and 3D QSAR CoMFA and CoMSIA studies for lead optimization, for designing of potent tumor necrosis factor alpha converting enzyme inhibitors

Discovery of Selective Small Molecular TACE Inhibitors for the Treatment of Rheumatoid Arthritis

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