Discovery of an N-(2-aminopyridin-4-ylmethyl)nicotinamide derivative: a potent and orally bioavailable NCX inhibitor

Kuramochi, Takahiro; Kakefuda, Akio; Yamada, Hiroyoshi; Tsukamoto, Issei; Taguchi, Taku; Sakamoto, Shuichi

doi:10.1016/j.bmc.2005.03.052

Cited by 16 publications

(20 citation statements)

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“…In this regard, pharmacological inhibitors have been developed as putative cardioprotective agents to reduce RM NCX1 activity and ameliorate the deleterious Ca 2+ c overload in cardiac tissue (12–14). While such NCX inhibitors favor pathophysiological cardiac RM NCX1 inhibition (13,15–18), their effects on the physiological Ca 2+ c extrusion via FM NCX1 activity in β-cells have not been determined. Theoretically, partial pharmacological inhibition of FM NCX1 activity in β-cells should delay Ca 2+ c clearance, leading to an increased Ca 2+ c exocytotic signal and enhanced insulin secretion that is sensitive to glucose.…”

mentioning

confidence: 99%

Inhibition of β-Cell Sodium-Calcium Exchange Enhances Glucose-Dependent Elevations in Cytoplasmic Calcium and Insulin Secretion

Hamming

Soliman²,

Webster³

et al. 2010

Diabetes

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OBJECTIVEThe sodium-calcium exchanger isoform 1 (NCX1) regulates cytoplasmic calcium (Ca2+c) required for insulin secretion in β-cells. NCX1 is alternatively spliced, resulting in the expression of splice variants in different tissues such as NCX1.3 and -1.7 in β-cells. As pharmacological inhibitors of NCX1 splice variants are in development, the pharmacological profile of β-cell NCX1.3 and -1.7 and the cellular effects of NCX1 inhibition were investigated.RESEARCH DESIGN AND METHODSThe patch-clamp technique was used to examine the pharmacological profile of the NCX1 inhibitor KB-R7943 on recombinant NCX1.3 and -1.7 activity. Ca2+ imaging and membrane capacitance were used to assess the effects of KB-R7943 on Ca2+c and insulin secretion in mouse and human β-cells and islets.RESULTSNCX1.3 and -1.7 calcium extrusion (forward-mode) activity was ∼16-fold more sensitive to KB-R7943 inhibition compared with cardiac NCX1.1 (IC50s = 2.9 and 2.4 vs. 43.0 μmol/l, respectively). In single mouse/human β-cells, 1 μmol/l KB-R7943 increased insulin granule exocytosis but was without effect on α-cell glucagon granule exocytosis. KB-R7943 also augmented sulfonylurea and glucose-stimulated Ca2+c levels and insulin secretion in mouse and human islets, although KB-R7943 was without effect under nonstimulated conditions.CONCLUSIONSIslet NCX1 splice variants display a markedly greater sensitivity to pharmacological inhibition than the cardiac NCX1.1 splice variant. NCX1 inhibition resulted in glucose-dependent increases in Ca2+c and insulin secretion in mouse and human islets. Thus, we identify β-cell NCX1 splice variants as targets for the development of novel glucose-sensitive insulinotropic drugs for type 2 diabetes.

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mentioning

confidence: 99%

Inhibition of β-Cell Sodium-Calcium Exchange Enhances Glucose-Dependent Elevations in Cytoplasmic Calcium and Insulin Secretion

Hamming

Soliman²,

Webster³

et al. 2010

Diabetes

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“…1), a highly potent NCX inhibitor, was found by screening newly synthesized benzyloxyphenyl derivatives for inhibition of Na i ϩ -dependent 45 Ca 2ϩ uptake into NCX1-transfected fibroblasts (Kuramochi et al, 2005a). It has been reported that YM-244769 derivatives are orally bioavailable and efficiently prevent ischemia/reperfusion-induced ventricular tachycardia and fibrillation in rats (Kuramochi et al, 2005b). YM-244769 is thus expected to be a novel anti-ischemic drug.…”

mentioning

confidence: 99%

YM-244769, a Novel Na⁺/Ca²⁺Exchange Inhibitor That Preferentially Inhibits NCX3, Efficiently Protects against Hypoxia/Reoxygenation-Induced SH-SY5Y Neuronal Cell Damage

Iwamoto¹,

Kita²

2006

Mol Pharmacol

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We investigated the pharmacological properties and interaction domains of N- (3-aminobenzyl)-6-{4-[(3-fluorobenzyl)oxy]phenoxy} nicotinamide (YM-244769), a novel potent Na ϩ /Ca 2ϩ exchange (NCX) inhibitor, using various NCX-transfectants and neuronal and renal cell lines. YM-244769 preferentially inhibited intracellular Na ϩ -dependent 45 Ca 2ϩ uptake via NCX3 (IC 50 ϭ 18 nM); the inhibition was 3.8-to 5.3-fold greater than for the uptake via NCX1 or NCX2, but it did not significantly affect extracellular Na ϩ -dependent 45 Ca 2ϩ efflux via NCX isoforms. We searched for interaction domains with YM-244769 by NCX1/NCX3-chimeric analysis and determined that the ␣-2 region in NCX1 is mostly responsible for the differential drug response between NCX1 and NCX3. Further cysteine scanning mutagenesis in the ␣-2 region identified that the mutation at Gly833 markedly reduced sensitivity to YM-244769. Mutant exchangers that display either undetectable or accelerated Na ϩ -dependent inactivation, had markedly reduced sensitivity or hypersensitivity to YM-244769, respectively. YM-244769, like 2-[2-[4-(4-nitrobenzyloxyl)phenyl]ethyl]isothiourea methanesulfonate (KB-R7943), protected against hypoxia/reoxygenation-induced cell damage in neuronal SH-SY5Y cells, which express NCX1 and NCX3, more efficiently than that in renal LLC-PK 1 cells, which exclusively express NCX1, whereas 2-[4-(4-nitrobenzyloxy)benzyl]thiazolidine-4-carboxylic acid ethyl ester (SN-6) suppressed renal cell damage to a greater degree than neuronal cell damage. These protective potencies consistently correlated well with their inhibitory efficacies for the Ca 2ϩ uptake via NCX isoforms existing in the corresponding cell lines. Antisense knockdown of NCX1 and NCX3 in SH-SY5Y cells confirmed that NCX3 contributes to the neuronal cell damage more than NCX1. Thus, YM-244769 is not only experimentally useful as a NCX inhibitor that preferentially inhibits NCX3, but also has therapeutic potential as a new neuroprotective drug.

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“…The novel NCX inhibitor, YM-244769, was also effective in prevention of ischemia-reperfusion-induced ventricular tachycardia and fibrillation in rats [62]. In contrast, neither preischemic nor postischemic administration of SEA0400 could influence the incidence of ischemia-reperfusioninduced arrhythmias in dogs, while the drug was shown to exert a suppressive effect on digitalis induced tachyarrhythmias [63].…”

Section: The Effects Of Acute Ncx1 Inhibition In Ventricular Arrhythmmentioning

confidence: 97%

Role of NCX1 and NHE1 in Ventricular Arrhythmia

Tóth

Varró

2011

Heart Rate and Rhythm

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Discovery of an N-(2-aminopyridin-4-ylmethyl)nicotinamide derivative: a potent and orally bioavailable NCX inhibitor

Cited by 16 publications

References 20 publications

Inhibition of β-Cell Sodium-Calcium Exchange Enhances Glucose-Dependent Elevations in Cytoplasmic Calcium and Insulin Secretion

Inhibition of β-Cell Sodium-Calcium Exchange Enhances Glucose-Dependent Elevations in Cytoplasmic Calcium and Insulin Secretion

YM-244769, a Novel Na⁺/Ca²⁺Exchange Inhibitor That Preferentially Inhibits NCX3, Efficiently Protects against Hypoxia/Reoxygenation-Induced SH-SY5Y Neuronal Cell Damage

Role of NCX1 and NHE1 in Ventricular Arrhythmia

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Discovery of an N-(2-aminopyridin-4-ylmethyl)nicotinamide derivative: a potent and orally bioavailable NCX inhibitor

Cited by 16 publications

References 20 publications

Inhibition of β-Cell Sodium-Calcium Exchange Enhances Glucose-Dependent Elevations in Cytoplasmic Calcium and Insulin Secretion

Inhibition of β-Cell Sodium-Calcium Exchange Enhances Glucose-Dependent Elevations in Cytoplasmic Calcium and Insulin Secretion

YM-244769, a Novel Na+/Ca2+Exchange Inhibitor That Preferentially Inhibits NCX3, Efficiently Protects against Hypoxia/Reoxygenation-Induced SH-SY5Y Neuronal Cell Damage

Role of NCX1 and NHE1 in Ventricular Arrhythmia

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YM-244769, a Novel Na⁺/Ca²⁺Exchange Inhibitor That Preferentially Inhibits NCX3, Efficiently Protects against Hypoxia/Reoxygenation-Induced SH-SY5Y Neuronal Cell Damage