N-(5-substituted) thiophene-2-alkylsulfonamides as potent inhibitors of 5-lipoxygenase

Beers, Scott A.; Malloy, Elizabeth A.; Wu, Wei; Wachter, Michael P.; Ansell, Justin; Singer, Monica; Steber, Michele; Barbone, Arminda G.; Kirchner, Thomas; Ritchie, David M.; Argentieri, Dennis

doi:10.1016/s0968-0896(97)00025-4

Cited by 37 publications

(21 citation statements)

References 7 publications

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“…8), was developed as 5-LOX inhibitor [160] that was subsequently found to inhibit COX-2 selectively over COX-1 [161]. This compound displayed significant anti-inflammatory activity in carrageenan-induced inflammation in canines [160] and inhibited the development of neurogenic edema induced by saphenous nerve stimulation [162]. L-652,343 was demonstrated to inhibit COX and 5-LOX in vitro and was efficacious in acute and chronic inflammation models in vivo [163, 164].…”

Section: Rationally Designed Multitarget Agentsmentioning

confidence: 99%

Rationally Designed Multitarget Agents Against Inflammation and Pain

Hwang

Wecksler

Wagner

et al. 2013

CMC

101

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Arachidonic acid (ARA) undergoes enzyme-mediated oxidative metabolism, resulting in the formation of a number of biologically active metabolites. For over a century, these biochemical transformations have been the target of numerous pharmacological drugs for inflammation and pain. In particular, non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) selective inhibitors (coxibs) are widely used in the treatment of inflammation and pain. However, gastrointestinal (GI) and cardiovascular adverse effects of NSAIDs and coxibs, and recent findings demonstrating that there are significant risks from the disruption of oxylipin levels when pharmacologically inhibiting a single ARA cascade metabolic pathway, have led to studies involving the simultaneous inhibition of multiple pathways in ARA cascade. These studies suggest that multitarget inhibition represents a new and valuable option to enhance efficacy or reduce side-effects in the treatment of inflammation and pain. This review focuses on the crosstalk within the three pathways of the ARA cascade (cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450)), and summarizes the current and future approaches of multitarget inhibitors for the treatment of eicosanoid driven inflammation and pain.

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Section: Rationally Designed Multitarget Agentsmentioning

confidence: 99%

Rationally Designed Multitarget Agents Against Inflammation and Pain

Hwang

Wecksler

Wagner

et al. 2013

CMC

101

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“…[72][73][74][75][76][77][78]; 3) thiophene derivatives (RWJ-63556) [79,80]; 4) pyrazoline derivatives (phenidone, BW-755C) [81]; 5) pyrrolizine derivatives (licofelone, etc.) [82][83][84][85].…”

Section: Drugs Able To Inhibit Both Cyclooxy-genases (Cox-1 And/or Comentioning

confidence: 99%

Dual Acting Anti-Inflammatory Drugs

Leone¹,

Ottani²,

Bertolini

2007

CTMC

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Drugs able to inhibit both cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) (dual acting anti-inflammatory drugs) have been designed in order to obtain compounds that retain the activity of classical nonsteroidal anti-inflammatory drugs (NSAIDs) while avoiding their main drawbacks. The classical NSAIDs display their anti-inflammatory action mainly through inhibition of COX and one of their main drawbacks is the curtailed production of gastroprotective prostaglandins (PGs) being associated with the concurrent increased production of the gastro-damaging and bronchoconstrictive leukotrienes (LTs). Leukotrienes and cysteinyl-leukotrienes are moreover pro-inflammatory and increase microvascular permeability. One of the leukotrienes (LTB(4)) is the most potent chemotactic agent and it induces chemotaxis of eosinophils, neutrophils and monocytes in the inflamed tissue, increases superoxide generation and proinflammatory cytokines production. It is further advantageous for a drug to have both COX and 5-LOX inhibiting activities because prostaglandins enhance leukotriene-mediated inflammation. Various structural families of dual inhibitors have been designed and several compounds are currently undergoing clinical development. In the post-COX-2 selective inhibitors era, these dual acting inhibitors may turn out to be promising new drugs to treat inflammatory diseases and possibly other diseases. Indeed, both COX-2 and 5-LOX are also involved in the development and progression of several types of cancer; in these conditions, selective inhibition of COX-2 alone may lead to a shunt of arachidonic acid metabolism towards the leukotriene pathway, and therefore the blockade of both COX-2 and 5-LOX may produce a better anticancer response. In addition, the dual inhibition of both COX and 5-LOX is neuroprotective by suppressing toxic actions of reactive microglia and macrophages, that are increased in aging brain and in age-related degenerative conditions, particularly Alzheimer's and Parkinson's diseases. Finally, the blockade of 5-LOX does not impair the synthesis of lipoxins (LXs), which are mainly produced by further lipoxygenation of 15-HPETE, and which have potent anti-inflammatory properties and can be considered as stop-signal mediators. Leukocyte 15-LOX and platelet 12-LOX by intercellular mechanism via leukocyte/platelet cell-cell interaction convert 15-HPETE into lipoxins.

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“…Two compounds (22 and 23), containing different scaffolds, showed modest activity (Table 1). Compound 23 was also found by "TripleCharge3D" in the first screening round (35 th ), with the orally active dual inhibitor RWJ-63556 (COX-2, IC 50 = 1.86 mm; 5-LO, IC 50 = 0.13 mm) [17] as the query (Supporting Information, figure S1 [5] ). Although only moderately active hits were obtained in the final screening round, notably, compound 23 contains a similar scaffold to that seen in compounds 1-4, suggesting shape resemblance between pyridine-imidazole-and thiazole-based 5-LO inhibitors (Figure 2 [18] Recently, Geronikaki et al identified a series of 2-thiazolylimino-5-arylidene-4-thiazolidinones with moderate activity against dual soybean lipoxygenase/COX-1.…”

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confidence: 99%

Scaffold‐Hopping Cascade Yields Potent Inhibitors of 5‐Lipoxygenase

et al. 2008

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Defensive chemicals such as the ink secretion of this marine gastropod mollusk—the sea hares Aplysia californica—are released following attacks from predators for protection. One might expect these secretions to be complex mixtures of products, given that they must work against a diversity of predators. In their Full Paper on , C. D. Derby et al. describe some of the chemical complexity of the ink of sea hares attributable to the enzyme “escapin”. Escapin is an L‐amino acid oxidase that oxidatively deaminates its major substrate, L‐lysine, to produce an equilibrium mixture of the molecules shown in this image. Photograph from Genny Anderson (Santa Barbara City College). No Abstract

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N-(5-substituted) thiophene-2-alkylsulfonamides as potent inhibitors of 5-lipoxygenase

Cited by 37 publications

References 7 publications

Rationally Designed Multitarget Agents Against Inflammation and Pain

Rationally Designed Multitarget Agents Against Inflammation and Pain

Dual Acting Anti-Inflammatory Drugs

Scaffold‐Hopping Cascade Yields Potent Inhibitors of 5‐Lipoxygenase

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