Acetylenic TACE inhibitors. Part 1. SAR of the acyclic sulfonamide hydroxamates

Levin, Jeremy I.; Chen, J.M.; Cheung, Katherine; Cole, Derek C.; Crago, C.; Santos, Efren Delos; Du, Xiaona; Khafizova, Gulnaz; MacEwan, Gloria; Niu, Chuansheng; Salaski, Edward J.; Zask, Arie; Cummons, Terri; Sung, Amy; Xu, Jun; Zhang, Y.; Xu, Weixin; Ayral‐Kaloustian, Semiramis; Jin, Guixian; Cowling, Rebecca; Barone, D.; Mohler, Kendall M.; Black, Roy A.; Skotnicki, J.S.

doi:10.1016/s0960-894x(03)00514-6

Cited by 50 publications

(26 citation statements)

References 21 publications

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“…Sulfonylated hydroxamates inhibit a variety of MMPs, but also inhibit other enzymes with an active site zinc moiety such as carbonic anhydrase isoenzymes. Sulphonamide hydroxamates also inhibit tumor necrosis factor converting enzyme (TACE), a member of the ADAM (a disintegrin and metalloproteinase), which are multidomain metalloproteinases with the disintegrin domain anchored in cell membranes [115,127]. In contrast to ADAM, ADAMTS (ADAMs with a thrombospondin motif) are secreted and lack a membrane anchor.…”

Section: Mmp Inhibitors and Potential Benefits In Varicose Veinsmentioning

confidence: 99%

Matrix Metalloproteinases in Venous Tissue Remodeling and Varicose Vein Formation

Raffetto¹,

Khalil²

2008

CVP

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Matrix metalloproteinases (MMPs) play a major role in extracellular matrix (ECM) turnover under both physiological and pathological conditions. Studies on venous tissues from experimental animals and humans identified several MMP subtypes, and showed significant changes in the expression and activity of specific MMPs during vein wall remodeling. Also, significant research has focused on the role of MMPs in chronic venous disease (CVD) and varicose vein formation in the lower extremities and their progression to thrombophlebitis and venous leg ulcer. Several hypotheses have been forwarded regarding the pathophysiological mechanisms underlying the relation between MMPs and the formation, progression and complications of varicose veins. The effects of MMPs on ECM degradation could result in significant venous tissue remodeling and degenerative and structural changes in the vein wall, leading to venous dilation and valve dysfunction. MMPs may also induce early changes in the endothelium and venous smooth muscle function in the absence of significant ECM degradation or structural changes in the vein wall. In addition, evidence suggests increased activity of MMPs in the advanced stages of chronic venous insufficiency (CVI) associated with skin changes and leg ulceration as well as in the wound fluid environment. Several pharmacological therapies and surgical strategies are being utilized in the management of varicose veins, with variable success and recurrence rates. Inhibition of MMPs may represent a novel therapeutic intervention to limit the progression of varicose veins to CVI and leg ulceration.

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Section: Mmp Inhibitors and Potential Benefits In Varicose Veinsmentioning

confidence: 99%

Matrix Metalloproteinases in Venous Tissue Remodeling and Varicose Vein Formation

Raffetto¹,

Khalil²

2008

CVP

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“…Sulfonamide hydroxamates inhibit a variety of MMPs [366], but inhibit other enzymes with an active site Zn 2+ moiety such as carbonic anhydrases and tumor necrosis factor converting enzyme (TACE), a member of ADAMs [333, 367]. Sultam hydroxamates are a group sulfonamide hydroxamate MMPIs with increased specificity toward MMP-2, -9 and -13 and an IC 50 for MMP-2 (1 nM) 1000 fold more selective over MMP-1 [357].…”

Section: Introductionmentioning

confidence: 99%

Matrix Metalloproteinases as Potential Targets in the Venous Dilation Associated with Varicose Veins

Khalil¹

2013

Current Drug Targets

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Varicose veins (VVs) are a common venous disease of the lower extremity characterized by incompetent valves, venous reflux, and dilated and tortuous veins. If untreated, VVs could lead to venous thrombosis, thrombophlebitis and chronic venous leg ulcers. Various genetic, hormonal and environmental factors may lead to structural changes in the vein valves and make them incompetent, leading to venous reflux, increased venous pressure and vein wall dilation. Prolonged increases in venous pressure and vein wall tension are thought to increase the expression/activity of matrix metalloproteinases (MMPs). Members of the MMPs family include collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs and others. MMPs are known to degrade various components of the extracellular matrix (ECM). MMPs may also affect the endothelium and vascular smooth muscle, causing changes in the vein relaxation and contraction mechanisms. ECs injury also triggers leukocyte infiltration, activation and inflammation, which lead to further vein wall damage. The vein wall dilation and valve dysfunction, and the MMP activation and superimposed inflammation and fibrosis would lead to progressive venous dilation and VVs formation. Surgical ablation is an effective treatment for VVs, but may be associated with high recurrence rate, and other less invasive approaches that target the cause of the disease are needed. MMP inhibitors including endogenous tissue inhibitors (TIMPs) and pharmacological inhibitors such as zinc chelators, doxycycline, batimastat and marimastat, have been used as diagnostic and therapeutic tools in cancer, autoimmune and cardiovascular disease. However, MMP inhibitors may have side effects especially on the musculoskeletal system. With the advent of new genetic and pharmacological tools, specific MMP inhibitors with fewer undesirable effects could be useful to retard the progression and prevent the recurrence of VVs.

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“…When paired with many zinc-binding groups, the 4-alkynylmethoxyphenyl motif imparts selectivity towards ADAM protease inhibition, and against MMP inhibition. [32][33][34][35] Nonetheless, in the course of a comprehensive SAR study of the 4-alkynylmethoxyphenyl paired to thiol zinc-binding groups, Bandarage et al 25,36 observed several inhibitors having this pairing that showed both MMP-2 and ADAM-17 inhibitory activity. Our structure-activity data for MMP-2 inhibition are consistent with their data.…”

Section: Discussionmentioning

confidence: 99%

Exploring the functional space of thiiranes as gelatinase inhibitors using click chemistry

Testero¹,

Llarrull²,

Fisher³

et al. 2011

Arkivoc

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A series of 4-[(triazolyl)methoxy]phenyl analogs of the phenoxyphenyl-substituted thiirane SB-3CT 1 was evaluated for its ability to inhibit gelatinases, members of the matrix metalloproteinase family of enzymes. The triazole segment of these inhibitors was assembled using the Meldal-Sharpless copper-catalyzed Huisgen dipolar cycloaddition of an azide and a terminal alkyne. While these triazole derivatives possessed fair activity as gelatinase inhibitors, an intermediate used in the dipolar cycloaddition, 4-(propargyloxy)phenyl derivative 2, showed very good activity (>50% inhibitory activity following a 3 h pre-incubation of 2 at a concentration of 3 µM) as an inhibitor of human matrix metalloproteinase-2.

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Acetylenic TACE inhibitors. Part 1. SAR of the acyclic sulfonamide hydroxamates

Cited by 50 publications

References 21 publications

Matrix Metalloproteinases in Venous Tissue Remodeling and Varicose Vein Formation

Matrix Metalloproteinases in Venous Tissue Remodeling and Varicose Vein Formation

Matrix Metalloproteinases as Potential Targets in the Venous Dilation Associated with Varicose Veins

Exploring the functional space of thiiranes as gelatinase inhibitors using click chemistry

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