Synthesis and structure–activity relationships of phenoxypyridine derivatives as novel inhibitors of the sodium–calcium exchanger

Kuramochi, Takahiro; Kakefuda, Akio; Yamada, Hiroyoshi; Sato, Ippei; Taguchi, Taku; Sakamoto, Shuichi

doi:10.1016/j.bmc.2004.07.038

Cited by 8 publications

(7 citation statements)

References 16 publications

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“…Kuramochi et al . synthesized phenoxypyridine derivatives as novel inhibitors of the sodium–calcium exchanger via condensation of compound 246 with 4‐benzyloxyphenol followed by debenzylation and O‐alkylation with 3‐fluorobenzylbromide gave compound 247 . Subsequent reduction of 247 followed by condensation with chloroacetic anhydride and alkylation with pyrrolidine afforded compound 249 .…”

Section: Sodium–calcium Exchanger Inhibitorsmentioning

confidence: 99%

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A Review: Synthesis and Medicinal Importance of Nicotinonitriles and Their Analogous

Gouda

Hussein

Helal

et al. 2018

Journal of Heterocyclic Chem

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Section: Sodium–calcium Exchanger Inhibitorsmentioning

confidence: 99%

“…Subsequent reduction of 247 followed by condensation with chloroacetic anhydride and alkylation with pyrrolidine afforded compound 249 . Hydrolysis of the cyano function of compound 247 followed by condensation with a selection of amines afforded compounds 250a – m (Scheme ) .…”

Section: Sodium–calcium Exchanger Inhibitorsmentioning

confidence: 99%

A Review: Synthesis and Medicinal Importance of Nicotinonitriles and Their Analogous

Gouda

Hussein

Helal

et al. 2018

Journal of Heterocyclic Chem

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“…The residue was recrystallized from AcOEt-CH 3 CN (5 : 2) to give 14 as a beige powder (231 mg, 33%): mp 115-116°C; Pharmacology The methods of 45 Ca influx assay and Cell necrosis assay were described in previous report. 23) …”

Section: N-(2-{4-[(3-fluorobenzyl)oxy]phenoxy}ethyl)-nј-(pyridin-4-ylmentioning

confidence: 99%

“…We have recently discovered reverse NCX inhibitors, such as 3, which we have reported elesewhere. 16,23,24) To create potent and selective reverse NCX inhibitors, we have now designed a novel class of NCX inhibitors based on 3, and in this paper describe the results of our work on the synthesis and structure-activity relationships (SAR) of this novel class of benzyloxyphenyl derivatives. …”

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confidence: 99%

“…13,23) The inhibitory effect on the forward mode of NCX activity was assayed by a cell necrosis assay, which also used NCX1.1-expressing CCL39 cells. 23,25) The inhibitory potencies of our novel compounds were thus evaluated in both reverse and forward NCX assays. These compounds were then compared to reference compounds KB-R7943 (1), SEA0400 (2) and compound 3.…”

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Discovery of N-(3-{4-[(3-Fluorobenzyl)oxy]phenoxy}propyl)-2-pyridin-4-ylacetamide as a Potent and Selective Reverse NCX Inhibitor

Kuramochi

Kakefuda

Yamada

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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Intracellular Ca2ϩ is of primary importance in the pathogenesis of ischemia and reperfusion injury in the myocardium. Recent studies have suggested that a massive Ca 2ϩ influx may occur as a consequence of Na ϩ -Ca 2ϩ exchange via the sodium-calcium exchanger (NCX) during reperfusion which, in turn, may be caused by an accumulation of Na ϩ via the sodium-hydrogen exchanger (NHE) during ischemia. 1,2)This results in an intracellular Ca 2ϩ overload, the detrimental effects of which include myocardial contracture, stunning, necrosis, and reperfusion arrhythmia.3-9) NCX functions in both reverse and forward modes, and it is well known that an overactive reverse NCX causes Ca 2ϩ overload. Inhibition of reverse NCX overactivity would effectively block this overload and prevent damage to the myocardium in ischemiareperfusion. Therefore, reverse NCX inhibitors are currently considered to be beneficial in treating disease states.10,11) Recently, quinazoline derivatives 12) and a series of benzyloxyphenyl derivatives [13][14][15][16] have been identified as NCX inhibitors. KB-R7943 (1) is one of the most widely known NCX inhibitors, and is used as a tool in heart and renal failure models, 17,18) and SEA0400 (2) is well known as a potent reverse NCX inhibitor that is efficacious in myocardial ischemia-reperfusion injury [19][20][21][22] (Fig. 1). We have recently discovered reverse NCX inhibitors, such as 3, which we have reported elesewhere. 16,23,24) To create potent and selective reverse NCX inhibitors, we have now designed a novel class of NCX inhibitors based on 3, and in this paper describe the results of our work on the synthesis and structure-activity relationships (SAR) of this novel class of benzyloxyphenyl derivatives. ChemistryCompounds 4a-e were converted into compounds 5a-e via O-alkylation with 1-(bromomethyl)-3-fluorobenzene. Desired compounds 6a-e were prepared from 5a-e by condensation with pyridin-4-ylmethylamine as shown in Chart 1. Intermediate 4e was synthesized from 7 via S-alkylation with the corresponding alkylbromide. Compounds 9a-c were obtained by O-alkylation of 8 15) with the corresponding alkylbromides followed by hydrolysis of the ester group. Compounds 10a-c were afforded by condensation with 9a-c and pyridin-4-ylmethylamine. Compound 8 was converted into a compound whose amino group was protected with a phthaloyl group, followed by deprotection of the phthaloyl group with hydrazine to give compound 11. Compound 12 was afforded via condensation of 11 with pyridin-4-ylacetic acid. Compound 13 was prepared by O-alkylation of 8 with tert-butyl(2-bromoethyl)carbamate followed by deprotection of the tert-butoxycarbonyl group. Desired compound 14 was obtained from 8 via condensation with bis(trichloromethyl)carbonate and pyridin-4-ylmethylamine. Results and DiscussionIn order to measure the inhibitory effect of the synthesized compounds on the reverse mode of NCX activity, an Na ϩ -dependent Ca 2ϩ influx assay was performed according to reported protocols, using 45 Ca and CCL39 cells stably expr...

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Synthesis and structure–activity relationships of 6-{4-[(3-fluorobenzyl)oxy]phenoxy}nicotinamide derivatives as a novel class of NCX inhibitors: a QSAR study

Kuramochi¹,

Kakefuda²,

Sato³

et al. 2005

Bioorganic & Medicinal Chemistry

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Synthesis and structure–activity relationships of phenoxypyridine derivatives as novel inhibitors of the sodium–calcium exchanger

Cited by 8 publications

References 16 publications

A Review: Synthesis and Medicinal Importance of Nicotinonitriles and Their Analogous

A Review: Synthesis and Medicinal Importance of Nicotinonitriles and Their Analogous

Discovery of N-(3-{4-[(3-Fluorobenzyl)oxy]phenoxy}propyl)-2-pyridin-4-ylacetamide as a Potent and Selective Reverse NCX Inhibitor

Synthesis and structure–activity relationships of 6-{4-[(3-fluorobenzyl)oxy]phenoxy}nicotinamide derivatives as a novel class of NCX inhibitors: a QSAR study

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