Peptidoleukotriene antagonists: Structural analogs of leukotriene D4 with special emphasis on CGP 45715A

Sprecher, Andreas von; Beck, Andreas; Sallmann, A; Breitenstein, Werner; Wiestner, Hansruedi; Kimmel, S.; Anderson, Gary P.; Subramanian, Naeha; Bray, M.A.

doi:10.1358/dof.1991.016.09.155671

Cited by 22 publications

(11 citation statements)

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“…Competition between LTD4 and CGP 45715A at the same receptor site(s) is in reasonable agreement with the results of Bray and co-workers [28,54]. CGP 45715A has been shown to be a potent and specific LTD4 antagonist in guinea-pig smooth muscle [28]. The displacement of LTD4 from their own receptor sites is not unanticipated, since CGP 45715A is a close structural analog of LTD4.…”

Section: Elimination Time Constant (S)supporting

confidence: 89%

“…In addition, at least one subtype of LTD4 receptors exists in lung membranes which is coupled via a stimulatory guanine nucleotide binding protein to phospholipase C [22,24]. Competition between LTD4 and CGP 45715A at the same receptor site(s) is in reasonable agreement with the results of Bray and co-workers [28,54]. CGP 45715A has been shown to be a potent and specific LTD4 antagonist in guinea-pig smooth muscle [28].…”

Section: Elimination Time Constant (S)supporting

confidence: 58%

“…stereocbemistry at the CGP 45715A skeleton is a precondition for a high LTD4 antagonizing potency [28].…”

Section: Elimination Time Constant (S)mentioning

confidence: 99%

“…Evidence from the effects of calcium channel blockers [24] and a specific 'intracellular calcium antagonist' [25] suggest that the calcium ions which are responsible for the induction of the LTD4-induced smooth muscle contraction come from intracellular rather than from extracellular sources [26]. In the course of the continuing search for novel and effective antagonists of the peptidoleukotrienes, a compound, CGP 45715A, has been synthesized at CibaGeigy which potently inhibited LTD4-induced broncho-constrictions in guinea-pig lung in vitro and in vivo [27,28]. Recently, it has also been shown that in healthy volunteers the drug efficiently antagonized bronchospasms triggered by a challenge with LTD4 [29].…”

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confidence: 99%

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The action of the peptidoleukotriene LTD4 on intracellular calcium in rat mesangial cells

Ochsner

1996

Experientia

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The dose-dependent effect of CGP 45715A on the LTD4-induced Ca2+ response of glomerular mesangial cells has been studied. Our results demonstrate that the LTD4-dependent increase in the cytosolic Ca2+ concentration primarily involves an InsP3-mediated release of Ca2+ from intracellular storage sites and to a minor extent an enhanced influx of Ca2+ through receptor-operated Ca2+ channels located in the plasma membrane. The action of CGP 45715A on the Ca2+ response is an inhibitory one and is convincingly explained by a displacement of LTD4 from its receptor site(s). The contractile effect of LTD4 on pulmonary smooth muscle is proposed to be mainly caused by a receptor-mediated hydrolysis of phosphatidylinositol-4,5-bisphosphate.

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Section: Elimination Time Constant (S)supporting

confidence: 89%

Section: Elimination Time Constant (S)supporting

confidence: 58%

“…stereocbemistry at the CGP 45715A skeleton is a precondition for a high LTD4 antagonizing potency [28].…”

Section: Elimination Time Constant (S)mentioning

confidence: 99%

mentioning

confidence: 99%

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The action of the peptidoleukotriene LTD4 on intracellular calcium in rat mesangial cells

Ochsner

1996

Experientia

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“…Extensive SAR studies guided by in vitro receptor binding assays revealed that the tetraene component of LTD 4 could be mimicked by more stable simple phenyl rings, the thiopeptide substituent could be replaced by an alkyl carboxylate, and the C 1 carboxylate was retained. 126 Stereochemistry of functional groups played an important role. The two antagonists 30 (pobilukast, SKB 104353) and 31 (sulukast, LY170680) retained the natural configuration of LTD 4 about the thioether linkage and hydroxyl group.…”

Section: Peptidyl Leukotriene Antagonists That Have Progressed To CLImentioning

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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COX‐2 Inhibitors and Leukotriene Modulators

Bell

Harris

Stewart

2003

Burger's Medicinal Chemistry and Drug Discovery

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Agents that modulate the effects of eicosanoids have proved to be important therapeutics. In the early 1990s a number of agents that modulate the actions or synthesis of leukotrienes were optimized and tested in asthma. This major effort provided for the approval of two CYSLT1 antagonists, montelukast and zafirlukast; and one 5‐lipoxygenase inhibitor, zileuton, which proved effective in the treatment of asthma. More recently, the breakthrough discovery of a second cyclooxygenase isozyme, COX‐2, provided the impetus for the discovery of selective COX‐2 agents. These agents, which include celecoxib, rofecoxib, and valdecoxib, have been shown to have significant anti‐inflammatory and analgesic effects while being gastric sparing, in contrast to nonselective cyclooxygenase inhibitors commonly referred to as NSAIDs. The gastric‐sparing properties of these agents and others currently in development should open new therapeutic modalities. One of the most exciting of these is in the prevention and treatment of cancer.

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Peptidoleukotriene antagonists: Structural analogs of leukotriene D4 with special emphasis on CGP 45715A

Cited by 22 publications

References 0 publications

The action of the peptidoleukotriene LTD4 on intracellular calcium in rat mesangial cells

The action of the peptidoleukotriene LTD4 on intracellular calcium in rat mesangial cells

Modulators of Leukotriene Biosynthesis and Receptor Activation

COX‐2 Inhibitors and Leukotriene Modulators

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