Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates

Levin, Jeremy I.; Chen, J.M.; Laakso, Leif M.; Du, Mila T.; Schmid, Jean; Xu, Weixin; Cummons, Terri; Xu, Jun; Jin, G.; Barone, D.; Skotnicki, J.S.

doi:10.1016/j.bmcl.2005.12.020

Cited by 43 publications

(7 citation statements)

References 22 publications

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“…Pharmacophore study A total data set of 198 molecules having inhibitory activity spanning over two log orders (3-1,000 nM) against TACE was collected from literature (Levin et al, 2001a(Levin et al, , b, 2002(Levin et al, , 2006Nelson et al, 2002;Zask et al, 2003Zask et al, , 2005. Biological activity data for all molecules was calculated using same assay method .…”

Section: Resultsmentioning

confidence: 99%

“…For modeling study, a data set of molecules having inhibitory activity against TACE and MMP-1 was selected from the literature (Levin et al, 2001a(Levin et al, , b, 2002(Levin et al, , 2006Levin, 2004;Nelson et al, 2002;Yamamoto et al, 1998;Zask et al, 2003;Zask et al, 2005). For the generation of pharmacophore models for TACE and MMP-1, training set of 3 and 2 molecules was selected on the basis of structural diversity (Table 1).…”

Section: Data Setmentioning

confidence: 99%

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Strategy for generation of new TACE inhibitors: pharmacophore and counter pharmacophore modeling to remove non-selective hits

Bahia

Silakari

2010

Med Chem Res

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Present study describes the ligand-based molecular modeling along with virtual screening (VS) approach for generation of new tumor necrosis factor-a converting enzyme (TACE) inhibitors. In ligand-based molecular modeling, two statistically reliable HipHop pharmacophore models Hip1 and counter pharmacophore (CP1) were generated using training set of 3 and 2 molecules, respectively. CP1 was generated using inhibitors of MMP-1 (matrix metalloproteinase-1), an important enzyme involved in musculoskeletal degradation. VS was performed with model Hip1 in in-house database of 1.2 million molecules. In addition, the retrieved molecules were screened with CP1. The combination of both models helped for generating new improved TACE inhibitor molecules.

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Section: Resultsmentioning

confidence: 99%

Section: Data Setmentioning

confidence: 99%

Strategy for generation of new TACE inhibitors: pharmacophore and counter pharmacophore modeling to remove non-selective hits

Bahia

Silakari

2010

Med Chem Res

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“…BMS-561392 or DPC-333 (Bristol-Myers Squibb Company) inhibits TACE activity with IC 50 value of 0.20 nM in in vitro study and its selectivity on TACE activity is more than 100-fold over other MMPs. 16) Apratastat (TMI-005; Wyeth Pharmaceuticals) shows TACE inhibitory activity with IC 50 value of 440 nM in in vitro. 17) Although both drugs show good in vitro profiles, clinical phase II trials had failed due to hepatotoxicity and lack of efficacy, respectively.…”

Section: Discussionmentioning

confidence: 99%

A Novel TNF-α Converting Enzyme (TACE) Selective Inhibitor JTP-96193 Prevents Insulin Resistance in KK-A<sup>y</sup> Type 2 Diabetic Mice and Diabetic Peripheral Neuropathy in Type 1 Diabetic Mice

Maekawa

Tadaki

Tomimoto

et al. 2019

Biological & Pharmaceutical Bulletin

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Tumor necrosis factor-α (TNF-α) converting enzyme/a disintegrin and metalloproteinase domain-containing protein 17 (TACE/ADAM17) is a key sheddase that releases TNF-α from its inactive precursor and is thought as a new drug target to inhibit TNF-α production. In the present study, pharmacological effects of a novel TACE selective inhibitor, JTP-96193, on type 2 diabetes and diabetic peripheral neuropathy (DPN) as its major complication was examined. Enzyme inhibitory activity of JTP-96193 on TACE and other ADAMs was measured in in vitro. High fat-induced obese mice and type 2 diabetic KK-A y mice were used to evaluate the effect of JTP-96193 on insulin resistance. Finally, streptozotocin (STZ)-induced diabetic mice were treated with JTP-96193 to evaluate the sciatic motor nerve conduction velocities (MNCV). JTP-96193 selectively inhibited human TACE activity with IC 50 value of 5.4 nM and showed more than 1800-fold selectivity against other matrix metalloproteinases. In mouse models of obesity and diabetes, JTP-96193 reduced the TNF-α release from the fat tissue and prevented development of diabetes and improved insulin resistance, respectively. Furthermore, JTP-96193 prevented delay of sciatic MNCV without any effects on blood glucose or insulin levels in STZ-induced diabetic mice. TACE inhibitor is effective on insulin resistance and DPN independent from glucose-lowering effect. These pharmacological properties of JTP-96193 may be helpful to treat type 2 diabetes accompanied by its microvascular complications.

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“…16 However, some structural differences between the active sites of matrix metalloproteinases and TACE motivate rational synthesis of specific TACE inhibitors. [20][21][22][23][24] Several studies have clarified that hydroxamate derivatives have potential to inhibit TACE, as they have ability to coordinate with zinc atom at the active site of TACE through their carbonyl and hydroxyl oxygens. 16,25 The aim of the current study was to generate a 3D-QSAR model based on the alignment-independent descriptors calculated for a set of hydroxamate TACE inhibitors in order to identify the structural features required for TACE inhibition.…”

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confidence: 99%

An alignment‐independent 3D‐QSAR study on series of hydroxamic acid‐based tumor necrosis factor‐α converting enzyme inhibitors

Alizadeh

Hamzeh‐Mivehroud

Sokouti

et al. 2016

Journal of Chemometrics

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Grid‐independent descriptors are extensively used in 3D quantitative structure‐activity relationship (3D‐QSAR) studies. These kinds of descriptors represent the spatial arrangement of the atoms in a 3D fashion. In the current study, we have developed a 3D‐QSAR model for a set of hydroxamic acid‐based derivatives as tumor necrosis factor‐α converting enzyme (TACE) inhibitors. The generated model revealed the importance of some main moieties in the potency of these compounds. Quinolinyl and hydroxamate moieties have the ability to act as hydrogen bond acceptors and hot spot points. On the other hand, phenyl ring can participate in hydrophobic contacts with the receptor. 3D‐QSAR analyses resulted in the partial least squares model of 3 latent variables with internal and external validation yielding q2 values of 0.66 and 0.73, respectively. The result of the current study can be used in designing of potent TACE inhibitors where inhibition of TACE enzyme is required, such as inflammatory diseases, atherosclerosis, osteoporosis, autoimmune disorders, allograft rejection, and cancer.

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Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates

Cited by 43 publications

References 22 publications

Strategy for generation of new TACE inhibitors: pharmacophore and counter pharmacophore modeling to remove non-selective hits

Strategy for generation of new TACE inhibitors: pharmacophore and counter pharmacophore modeling to remove non-selective hits

A Novel TNF-α Converting Enzyme (TACE) Selective Inhibitor JTP-96193 Prevents Insulin Resistance in KK-A<sup>y</sup> Type 2 Diabetic Mice and Diabetic Peripheral Neuropathy in Type 1 Diabetic Mice

An alignment‐independent 3D‐QSAR study on series of hydroxamic acid‐based tumor necrosis factor‐α converting enzyme inhibitors

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