Design and synthesis of novel 9-substituted-7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,3-b]- and [2,3-b]-1,5-oxazocin-6-ones as NK1 antagonists

Seto, Shigeki; Tanioka, Asao; Ikeda, Makoto; Izawa, Shigeru

doi:10.1016/j.bmcl.2004.12.091

Cited by 25 publications

(11 citation statements)

References 18 publications

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“…There are continuing efforts to explore the therapeutic potential of novel compounds that interfere with the endogenous effects of these neuropeptides by either blocking the endogenous receptors for SP and CGRP or by causing a depletion of SP from sensory nerve endings, thus indirectly reducing its inflammatory activity (Appendino et al, 2005;Seto et al, 2005;Ambalavanar et al, 2006). In contrast, our approach for reducing inflammation caused by SP and CGRP focuses on interfering with the synthesis of these neuropeptides by inhibiting the activity of PAM, the rate-limiting enzyme required for their endogenous bioactivation.…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Effects of 4-Phenyl-3-butenoic Acid and 5-(Acetylamino)-4-oxo-6-phenyl-2-hexenoic Acid Methyl Ester, Potential Inhibitors of Neuropeptide Bioactivation

Bauer¹,

Sunman²,

Foster³

et al. 2006

J Pharmacol Exp Ther

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Substance P (SP) and calcitonin gene-related peptide (CGRP) are well established mediators of inflammation. Therefore, inhibition of the biosynthesis of these neuropeptides is an attractive potential strategy for pharmacological intervention against a number of inflammatory diseases. The final step in the biosynthesis of SP and CGRP is the conversion of their glycineextended precursors to the active amidated peptide, and this process is catalyzed by sequential action of the enzymes peptidylglycine ␣-monooxygenase (PAM) and peptidylamidoglycolate lyase. We have demonstrated previously that 4-phenyl-3-butenoic acid (PBA) is a PAM inhibitor, and we have also shown that in vivo inhibition of serum PAM by PBA correlates with this compound's ability to inhibit carrageenan-induced edema in the rat. Here we demonstrate the ability of PBA to inhibit all three phases of adjuvant-induced polyarthritis (AIP) in rats; this represents the first time that an amidation inhibitor has been shown to be active in a model of chronic inflammation. We recently introduced 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid (AOPHA) as one of a new series of mechanismbased amidation inhibitors. We now report for the first time that AOPHA and its methyl ester (AOPHA-Me) are active inhibitors of serum PAM in vivo, and we show that AOPHA-Me correspondingly inhibits carrageenan-induced edema in rats in a dose-dependent manner. Neither PBA nor AOPHA-Me exhibits significant cyclooxygenase (COX) inhibition in vitro; thus, the anti-inflammatory activities of PBA and AOPHA-Me are apparently not a consequence of COX inhibition. We discuss possible pharmacological mechanisms that may account for the activities of these new antiinflammatory compounds.A number of neuropeptides, such as calcitonin gene-related peptide (CGRP), neuropeptide Y, substance P (SP), and vasoactive intestinal polypeptide, are initially synthesized as glycine-extended precursors, which are then converted to the bioactive C-terminal amidated form. Amidation is a two-step process catalyzed by the sequential actions of peptidylglycine ␣-monooxygenase (PAM; EC 1.14.17.3) and peptidylamidoglycolate lyase (EC 4.3.2.5). The monooxygenase first catalyzes ␣-hydroxylation of the glycine-extended precursor, and the lyase then catalyzes conversion of this ␣-hydroxyglycine derivative to the C-terminally amidated peptide (Katopodis et al., , 1991Ping et al., 1992). In the case of SP and CGRP, their release from nerves, as well as inflammatory cells, has been shown to facilitate a number of inflammatory events, including increased vascular permeability, chemotaxis, and release of inflammatory mediators, such as cytokines, eicosanoids, and histamine (Pernow, 1983;Matucci-Cernic and Partsch, 1992;Haines et al., 1993;Holzer and Holzer-Petsche, 1997). Further evidence demonstrating the inflammatory capacity of SP was noted when SP receptor (neurokinin-1 receptor) knockout mice developed significantly less inflammation than controls after treatment with a phlogistic agent (Bozic et al., 1996)....

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Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Effects of 4-Phenyl-3-butenoic Acid and 5-(Acetylamino)-4-oxo-6-phenyl-2-hexenoic Acid Methyl Ester, Potential Inhibitors of Neuropeptide Bioactivation

Bauer¹,

Sunman²,

Foster³

et al. 2006

J Pharmacol Exp Ther

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“…SP can induce IL-1, a well known cytokine in the airway inflammation. Binding of SP to NK 1 receptors has been associated with transmission of stress signals, pain, contraction of smooth muscles and inflammation [34]. Also, involvement NK 1 receptor has been suggested in mucous secretion and plasma protein extravasation with consequent bronchial obstruction in the airways [35].…”

Section: Relationship Between Neurogenic Pathways and Immunobiology Omentioning

confidence: 99%

Allergic rhinitis: An update on disease, present treatments and future prospects

Mandhane¹,

Shah²,

Thennati³

2011

International Immunopharmacology

110

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“…The binding of substance P to NK 1 receptors is also related to the transmission of stress signals, inducing mood disorders and anxiety [12,13]. NK 1 receptor antagonists selectively suppress the substance P-mediated actions, showing antidepressant, anxiolytic, and antiemetic properties [14].…”

Section: Introductionmentioning

confidence: 99%

“…▶table 2 1 H NMR data of compounds 1a-3b (δ in ppm, J in Hz, 600 MHz) 13. C NMR data of compounds 1a-3b (δ in ppm, J in Hz, 150 MHz).…”

mentioning

confidence: 99%

Tetra-cis/trans-Coumaroyl Polyamines as NK1 Receptor Antagonists from Matricaria chamomilla

Park

Song

Kim

2017

PMIO

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Supporting information 1D and 2D NMR spectra of 1a/1b, 2a/2b and 3a/3b are available online at http://www.thieme-connect.de/products. AbStr Ac tCis-trans isomers of N 1 ,N 5 ,N 9 ,N 14 -tetra-p-coumaroyl thermospermines and N 1 ,N 5 ,N 10 ,N 14 -tetra-p-coumaroyl spermines were found in Matricaria chamomilla, German chamomile using countercurrent chromatography with methylene chloride-methanol-water (1:1:1, v/v/v). Their structures were elucidated based on spectroscopic and spectrometric data (1D and 2D NMR, and HRESIMS). The antagonistic activity against the neurokinin-1 receptor was examined by a calcium assay, measuring the cytosolic fluorescence triggered by substance P binding to the receptor. The compounds 1a/1b, 2a/2b, and 3a/3b potently suppressed the calcium flux compared to the known antagonist L-703,606 oxalate, indicating that the compounds competitively inhibited the binding of substance P. They also suppressed substance P-induced proliferation in MDA-MB-453, the HER2-amplified breast cancer cell line. It is suggested that tetracoumaroyl thermospermines and tetracoumaroyl spermines are promising antagonists, exerting positive effects on substance P/neurokinin-1 receptor-related diseases.

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Design and synthesis of novel 9-substituted-7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,3-b]- and [2,3-b]-1,5-oxazocin-6-ones as NK1 antagonists

Cited by 25 publications

References 18 publications

Anti-Inflammatory Effects of 4-Phenyl-3-butenoic Acid and 5-(Acetylamino)-4-oxo-6-phenyl-2-hexenoic Acid Methyl Ester, Potential Inhibitors of Neuropeptide Bioactivation

Anti-Inflammatory Effects of 4-Phenyl-3-butenoic Acid and 5-(Acetylamino)-4-oxo-6-phenyl-2-hexenoic Acid Methyl Ester, Potential Inhibitors of Neuropeptide Bioactivation

Allergic rhinitis: An update on disease, present treatments and future prospects

Tetra-cis/trans-Coumaroyl Polyamines as NK1 Receptor Antagonists from Matricaria chamomilla

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