Orally Active MMP-1 Sparing α-Tetrahydropyranyl and α-Piperidinyl Sulfone Matrix Metalloproteinase (MMP) Inhibitors with Efficacy in Cancer, Arthritis, and Cardiovascular Disease

Becker, Daniel P.; Barta, Thomas E.; Bedell, Louis J.; Boehm, Terri L.; Bond, Brian R.; Carroll, Jeffery N.; Carron, Chris P.; DeCrescenzo, Gary; Easton, Alan M.; Freskos, John N.; Funckes-Shippy, Chris L.; Heron, Marcia I.; Hockerman, Susan L.; Howard, Carol Pearcy; Kiefer, James R.; Li, Madeleine H.; Mathis, Karl J.; McDonald, Joseph J.; Mehta, Pramod P.; Munie, Grace E.; Sunyer, Teresa; Swearingen, Craig; Villamil, Clara I.; Welsch, Dean J.; Williams, Jennifer M.; Yu, Ying; Yao, Jun

doi:10.1021/jm100669j

Cited by 89 publications

(80 citation statements)

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“…Clinical trials for many of these agents showed poor pharmacokinetic and lack of specificity as anticancer or for cardiovascular diseases. Thus they showed many undesired side effects [2,7,27,40]. The implication of MMPs and TIMPs in the dental disorders is vast and promising but due to complicated types very little is known the physiology of each of the MMPs.…”

Section: Matrix Metalloproteinases (Mmps)mentioning

confidence: 99%

Recent Advances in Role of Matrix metalloproteinases in Some Dental Diseases

MH¹,

Sabahat²

2016

IJDOS

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Section: Matrix Metalloproteinases (Mmps)mentioning

confidence: 99%

Recent Advances in Role of Matrix metalloproteinases in Some Dental Diseases

MH¹,

Sabahat²

2016

IJDOS

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“…[3,8] Two structures, representing the two classes of inhibitors, were selected from the Protein Data Bank (PDB) as templates: 3KRY [8] (1.90 ) and 3KEK [3b] (1.97 ). These two conformations were selected as targets for docking studies.…”

mentioning

confidence: 99%

“…The binding site of MMP-13 in the open S1' conformation (seen in both 3KRY [8] and of 3KEK [3b] ) was analyzed to evaluate its suitability for docking experiments. In both complexes, the amino acid sequences and their spatial dispositions are very similar (RMSD = 0.740 ).…”

mentioning

confidence: 99%

“…[3b] ; 0.134 for 3KRY [8] ; the results are average for all conformations obtained by docking simulations).…”

mentioning

confidence: 99%

“…Moreover, the distance of compound 1 (chelating portion) from the Zn 2 + cation is 9.7 on average. The results obtained by docking experiments using the enzyme structure 3KRY [8] predict that the distance between compound 1 and the zinc atom is too great for a close interaction (~7.50 ). The amino acids involved in this case are Tyr 244 and Leu 184, and we also noted possible coordination with water molecules (Figure 3).…”

mentioning

confidence: 99%

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Benzisothiazolyliminothiazolidin‐4‐ones with Chondroprotective Properties: Searching for Potent and Selective Inhibitors of MMP‐13

et al. 2011

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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.[1] Nonselective inhibition of different MMPs by the early inhibitors appears to be the reason for their toxicity and limited efficacy.[2] Recent findings suggest that selective inhibition of MMP-13 could avoid toxicity and that non-zinc-chelating MMP inhibitors appear to be the most promising agents toward achieving selectivity, since the allosteric binding sites are not shared by different MMPs. Biochemical, histological and clinical models support this findings. [1b,3] Therefore, effective MMP-13 inhibition would be a novel, disease-modifying therapy for the treatment of osteoarthritis.Our recent efforts in the search for new agents with antidegenerative activity, as evaluated in human chondrocyte cultures stimulated by IL-1b, have resulted in the discovery of a series of heteroarylimino-4-thiazolidinones that significantly inhibit MMPs and other inflammatory mediators.[4] Among these, a potent and selective MMP-13 inhibitor has been identified (MMP-13, IC 50 = 0.036 mm; MMP-3, IC 50 > 100 mm) based upon a 2-(benzo [d]isothiazol-3-ylimino)-5-(4-methoxybenzylidene)thiazolidin-4-one scaffold (1; Figure 1). The presence of the electron-donating, moderately hydrophilic and bulky methoxy group at the benzylidene para position in compound 1 afforded the highest improvement in MMP-13 inhibition among all the heteroarylimino analogues of the series. This prompted us to explore the structure-activity relationship within the three positional methoxybenzylidene isomers 1-3 and evaluate the binding mode between compounds 1-3 and MMP-13 by molecular modeling.Herein, we describe the synthesis, the in vitro evaluation and the docking studies of compounds 1-3. The synthesis of the studied compounds was accomplished as illustrated in Scheme 1. Target compounds 1-3 were prepared from 2-(benzo[d]isothiazol-3-ylimino)thiazolidin-4-one (a; Scheme 1), recently synthesized in our laboratory, by reaction with the appropriately substituted aryl aldehyde according to previously reported protocols.[5]MMP-13 inhibition (IC 50 ) was investigated by evaluating the ability of compounds 1-3 to prevent the hydrolysis of the appropriate fluorescence-quenched peptide substrate.[6] To get a deeper insight into the mechanism of chondroprotective action of compounds 1-3, their effect in cultures of human chondrocytes, stimulated by IL-1b, was evaluated by determining cell viability, nitric oxide (NO) and glycosaminoglycan (GAG) levels.[1c] In addition, the antioxidant properties of the compounds were tested by means of an oxygen radical absorbance capacity (ORAC) assay and by determining the free radical scavenging ability of the molecules through measuring the extent of their interaction with the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH). [7] As shown in Table 1, modification of the methoxy substituent position afforded a significant decrease in the MMP-13 inhibitory activity of compounds 2 and 3 (IC...

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2018

Privileged Structures in Drug Discovery

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Orally Active MMP-1 Sparing α-Tetrahydropyranyl and α-Piperidinyl Sulfone Matrix Metalloproteinase (MMP) Inhibitors with Efficacy in Cancer, Arthritis, and Cardiovascular Disease

Cited by 89 publications

References 73 publications

Recent Advances in Role of Matrix metalloproteinases in Some Dental Diseases

Recent Advances in Role of Matrix metalloproteinases in Some Dental Diseases

Benzisothiazolyliminothiazolidin‐4‐ones with Chondroprotective Properties: Searching for Potent and Selective Inhibitors of MMP‐13

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