A novel series of selective leukotriene antagonists: exploration and optimization of the acidic region in 1,6-disubstituted indoles and indazoles

Yee, Ying K.; Bernstein, Peter R; Adams, Edward J.; Brown, Frederick J.; Cronk, Laura A.; Hebbel, Kevin C.; Vacek, Edward P.; Krell, Robert D.; Snyder, David W.

doi:10.1021/jm00171a018

Cited by 56 publications

(24 citation statements)

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“…the effect of pilocarpine on the guinea-pig isolated trachea and the effect of histamine on the guinea-pig isolated ileum whilst 5-amino indazole is a relatively potent inhibitor of carbachol-induced gastric acid secretion in the rat (Pinelli et al, 1989). More chemically complex indazole derivatives which inhibit lipoxygenase enzyme activity (Foster et al, 1989) or antagonize either leukotriene (Yee et al, 1990) or 5-HT3 (Robertson et al, 1990) receptors have also been synthesized. Perhaps of greater relevance to the present study is benzydamine, an indazole derivative, with pronounced antinociceptive activity which has been recognised for over two decades (Silvestrini et al, 1966;Lisciani et al, 1968).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the novel nitric oxide synthase inhibitor 7‐nitro indazole and related indazoles: antinociceptive and cardiovascular effects

Moore

Wallace

Gaffen

et al. 1993

British J Pharmacology

443

171

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1 7-Nitro indazole (7-NI, 10-50mgkg-'), 6-nitro indazole and indazole (25-100mgkg-') administered i.p. in the mouse produce dose-related antinociception in the late phase of the formalin-induced hindpaw licking and acetic acid-induced abdominal constriction assays. The EDm values (mg kg-') were as follows: 7-NI (27.5 and 22.5), 6-nitro indazole (62.5 and 44.0) and indazole (41.0 and 48.5) in the two assays respectively. 3-Indazolinone, 6 amino indazole and 6-sulphanilimido indazole (all 50 mg kg-') were without effect. With the exception of 5-nitro indazole (50 mg kg-') which produced sedation, none of the other indazole derivates examined caused overt behavioural changes. 2 The antinociceptive effect of 7-NI (25 mg kg-', i.p.) in the late phase of the formalin-induced hindpaw licking assay was partially (46.7 ± 16.2%, n = 18) reversed by pretreatment with L-but not D-arginine (both 50 mg kg', i.p.). 3 The time course of 7-NI induced antinociception in the mouse was correlated with inhibition of brain (cerebellum) nitric oxide synthase (NOS) activity. Maximum antinociceptive activity and NOS inhibition were detected 18-30 min following i.p. administration. In contrast, no antinociceptive effect or inhibition of cerebellar NOS was detected 75 min post-injection. 4 7-NI, 6-nitro indazole, indazole, 3-indazolinone and 6-amino indazole (all 50 mg kg-') failed to influence mean arterial pressure (MAP) over the 45 min after i.p. administration in the anaesthetized mouse. Similarly, 7-NI (25 mg kg-') administered i.v. in the anaesthetized rat did not increase MAP or influence the vasodepressor effect of i.v. injected acetylcholine (ACh) over the same period. 0.06 fLM, n = 6) in phenylephrine-precontracted rabbit aortic rings. 6 These data provide further evidence that antinociception following administration of 7-NI in the mouse results from inhibition of central NOS activity and is not associated with inhibition of in vivo vascular endothelial cells NOS. Accordingly, 7-NI (or a derivative thereof) may provide an alternative approach to the development of novel antinociceptive drugs.

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Section: Discussionmentioning

confidence: 99%

Characterization of the novel nitric oxide synthase inhibitor 7‐nitro indazole and related indazoles: antinociceptive and cardiovascular effects

Moore

Wallace

Gaffen

et al. 1993

British J Pharmacology

443

171

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“…44–46 The acylsulfonamide (or sulfonimide) has a similar geometry and pK a as a carboxylic acid, and it was successfully applied as a cysteinyl leukotriene (LTE4) receptor antagonist that demonstrated greater activity than the parent carboxylic acid. 47 Acylsulfonamides were also chosen because they are convenient to synthesize from the corresponding carboxylic acid. Though slightly larger than a carboxylic acid, 48 tetrazoles faithfully reproduce their trigonal planar shape and acidity (pK a : 4.5–4.9), as the tetrazole anion is stabilized by delocalization.…”

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confidence: 99%

LAT1 activity of carboxylic acid bioisosteres: Evaluation of hydroxamic acids as substrates

Zur

Chien

Augustyn

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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Large neutral amino acid transporter 1 (LAT1) is a solute carrier protein located primarily in the blood-brain barrier (BBB) that offers the potential to deliver drugs to the brain. It is also up-regulated in cancer cells, as part of a tumor’s increased metabolic demands. Previously, amino acid prodrugs have been shown to be transported by LAT1. Carboxylic acid bioisosteres may afford prodrugs with an altered physicochemical and pharmacokinetic profile than those derived from natural amino acids, allowing for higher brain or tumor levels of drug and/or lower toxicity. The effect of replacing phenylalanine’s carboxylic acid with a tetrazole, acylsulfonamide and hydroxamic acid (HA) bioisostere was examined. Compounds were tested for their ability to be LAT1 substrates using both cis-inhibition and trans-stimulation cell assays. As HA-Phe demonstrated weak substrate activity, its structure-activity relationship (SAR) was further explored by synthesis and testing of HA derivatives of other LAT1 amino acid substrates (i.e. Tyr, Leu, Ile, and Met). The potential for a false positive in the trans-stimulation assay caused by parent amino acid was evaluated by conducting compound stability experiments for both HA-Leu and the corresponding methyl ester derivative. We concluded that HA’s are transported by LAT1. In addition, our results lend support to a recent account that amino acid esters are LAT1 substrates, and that hydrogen bonding may be as important as charge for interaction with the transporter binding site.

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“…The general formula 93 shows possible modifications of the skeleton. The lead structures 94 and 95 contain central heterocyclic template (indazole or indole) and one-carbon connecting chain to the 3-methoxybenzoic acid fragment [78][79][80]. The antiasthmatic zafirlukast (Accolate ® , 95) was prepared by means of further refinement in this series as the most active compound of Zeneca [81].…”

Section: Peptidoleukotriene Receptor Antagonistsmentioning

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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A novel series of selective leukotriene antagonists: exploration and optimization of the acidic region in 1,6-disubstituted indoles and indazoles

Cited by 56 publications

References 0 publications

Characterization of the novel nitric oxide synthase inhibitor 7‐nitro indazole and related indazoles: antinociceptive and cardiovascular effects

Characterization of the novel nitric oxide synthase inhibitor 7‐nitro indazole and related indazoles: antinociceptive and cardiovascular effects

LAT1 activity of carboxylic acid bioisosteres: Evaluation of hydroxamic acids as substrates

5-Lipoxygenase, Leukotrienes Biosynthesis and Potential Antileukotrienic Agents

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