Rationally designed, potent competitive inhibitors of leukotriene biosynthesis

Corey, E. J.; Cashman, John R.; Kantner, Steven S.; Wright, Stephen W.

doi:10.1021/ja00317a064

Cited by 85 publications

(42 citation statements)

References 1 publication

(1 reference statement)

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“…There is chemical and computational evidence indicating that arachidonic acid, the parent fatty acid of anandamide, favors a bent or looped conformation in which the carbonyl group is proximal to the C14-C15 olefinic bond. The chemical evidence for such a conformation includes the highly regiospecific intramolecular epoxidation of arachidonyl peracid [103] and the facile macrolactonization of the C20 hydroxyl methyl arachidonate [104]. These experimental results are corroborated by molecular dynamics calculations [105] which indicate that indeed a bent conformation is thermodynamically favorable.…”

Section: ) Tail N-pentyl Group Modificationsmentioning

confidence: 85%

Natural and Synthetic Endocannabinoids and Their Structure-Activity Relationships

Palmer

Khanolkar²,

Makriyannis³

2000

CPD

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During the past several years, cannabinoid biology has witnessed marked advances that has propelled it to the forefront of biomedical research. These new developments have also provided an opportunity to examine the physiological and biochemical events underlying the use and abuse of cannabis as well as elucidating the biological role of the endogenous cannabinoid ligands (endocannabinoids). The biological targets for endocannabinoids include the cannabinoid receptors (CB1 and CB2), the enzyme anandamide amidohydrolase (AAH), and the carrier protein referred to as the anandamide transporter (ANT). The identification of arachidonylethanolamide (anandamide, AEA) as an endogenous cannabinoid has been an important development in cannabinoid research which has led to the identification of two proteins associated with cannabinoid physiology in addition to the CB1 and CB2 receptors. These proteins are anandamide amidohydrolase (AAH), an enzyme responsible for the hydrolytic breakdown of anandamide and the anandamide transporter (ANT), a carrier protein involved in the transport of anandamide across the cell membrane. Evidence obtained so far suggests that these two proteins, in combination, are responsible for the termination of the biological actions of anandamide. Also, the discovery of anandamide has revealed a novel class of more selective agents possessing somewhat different pharmacological properties than the cannabinoids. A number of such analogs have now been reported many of which possess markedly improved cannabinoid receptor affinities and metabolic stabilities compared to those of the parent ligand. Generally, anandamide and all known analogs exhibit significant selectivities with high affinities for the CB1 receptor and modest to very low affinity for the CB2 receptor. In a relatively short period of time, pharmacological and biochemical studies have confirmed initial speculations that anandamide is either a neuromodulator or neurotransmitter and has significantly advanced our understanding of cannabinoid biochemistry. This summary seeks to define the pharmacology of endocannabinoids and to focus on the structure-activity relationships (SAR) of anandamide for the CB1 cannabinoid receptor.

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Section: ) Tail N-pentyl Group Modificationsmentioning

confidence: 85%

Natural and Synthetic Endocannabinoids and Their Structure-Activity Relationships

Palmer

Khanolkar²,

Makriyannis³

2000

CPD

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“…Nalkyl derivatives of arachidonohydroxamic acid 34 [46] were the first compounds prepared. Although the skeleton of these compounds was modified 35-38, biological half-time prolongation was not achieved and their R&D was terminated.…”

Section: Iron Chelating Compoundsmentioning

confidence: 99%

5-Lipoxygenase, Leukotrienes Biosynthesis and Potential Antileukotrienic Agents

Jampílek¹,

Doležal²,

Opletalová³

et al. 2006

CMC

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Leukotrienes play an important role in the inflammatory process accompanying allergic diseases of respiratory, gastrointestinal and dermatological systems. Leukotrienes are generated from arachidonic acid as a result of the 5-lipoxygenase action. This paper deals with 5-lipoxygenase action mechanism and the following biosynthesis of all leukotrienes. In this article, potential antileukotrienic agents are classified according to their mechanism of action. The original antileukotrienic compounds of the Research Institute for Pharmacy and Biochemistry in Prague (VUFB), Czech Republic are presented in a separate chapter of the paper.

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“…The first validation of this hypothesis was the synthesis of arachidonohydroxamic acid as a potent in vitro inhibitor of 5-LO. 17 Low molecular weight, non-lipid hydroxamates were subsequently identified that were also potent in vitro inhibitors. This strategy of inhibitor design was elaborated using various 5-substituted-6,8,11,14-eicosatetraenoic acid (5-HETE) analogs 18,19 and 15-HETE templates.…”

Section: -Lipoxygenase Inhibitors That Have Progressed To Clinical Ementioning

confidence: 99%

Modulators of Leukotriene Biosynthesis and Receptor Activation

1996

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IntroductionThe history of leukotriene (LT) research has been documented in numerous articles and reviews since the discovery of the LT biosynthetic pathway 1 and the delineation of the various chemical structures involved in the pathway and their total synthesis. 2 Three previous Perspective articles have provided periodic updates, the first in 1981, 3 the second 1 decade later covering LT receptor antagonists, 4 and the third in 1992 covering LT biosynthesis inhibitors. 5 With this background, the task of this Perspective is to update the status of LT intervention research by providing an overview of the leading enzyme inhibitors and receptor antagonists as well as the status of clinical trials with these agents and how the latter are influencing the development of new therapeutic modalities for the treatment of inflammation and allergy.The clinical proof-of-concept for LT intervention has taken longer than expected considering that the biosynthesis and chemical composition of LTs were delineated by 1979. It is now clear that LT intervention therapy represents a promising new modality for the treatment of asthma. Several compounds including the 5-lipoxygenase (5-LO) inhibitor zileuton (1) and the cysteinyl LT antagonist zafirlukast (2) have completed pivotal clinical trials, while several other LT modulators are progressing to this stage. Within a few years the therapeutic potential of these new agents in asthma and other inflammatory and allergic disorders will be evident. Leukotriene Intervention StrategiesLeukotriene Biosynthesis. Leukotrienes are biosynthesized via the 5-LO (arachidonate:oxygen 5-oxidoreductase, EC 1.13.11.34) pathway of arachidonic acid (AA) metabolism ( Figure 1). The 5-LO product LTA 4 is a pivotal reactive epoxide intermediate in an important branch in the biosynthetic pathway that is further metabolized by either (i) stereoselective hydration by LTA 4 hydrolase to LTB 4 or (ii) glutathione addition by LTC 4 synthase to LTC 4 . Successive amino acid cleavage steps convert LTC 4 to LTD 4 and then to LTE 4 . The cysteinyl LTs (LTC 4 , LTD 4 , LTE 4 ) are the constituents of the biological substance previously known as slowreacting substance of anaphlyaxis (SRS-A). 6 LTB 4 is a very potent neutrophil chemotactic agent, inducing neutrophil adherence to endothelial cells, degranulation, and modulation of cytokine production. The biosynthesis, release, and recovery of LTs from specific cells involved in inflammatory disorders together with the observed ability of these products to mimic aspects of disease support their involvement as mediators of inflammatory and allergic disorders. 7,8 Despite such circumstantial evidence, confirmation of the pathophysiological role of these mediators requires selective blockade of their actions.At the outset of research efforts in the LT area, it was not entirely clear which LTs or subsequent metabolites were the predominant mediators of a particular human disorder. LTs are short-lived, being rapidly converted to inactive metabolites, and prolonged expressi...

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Rationally designed, potent competitive inhibitors of leukotriene biosynthesis

Cited by 85 publications

References 1 publication

Natural and Synthetic Endocannabinoids and Their Structure-Activity Relationships

Natural and Synthetic Endocannabinoids and Their Structure-Activity Relationships

5-Lipoxygenase, Leukotrienes Biosynthesis and Potential Antileukotrienic Agents

Modulators of Leukotriene Biosynthesis and Receptor Activation

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