新型浓缩核苷转运蛋白2抑制剂通过抑制嘌呤核苷的肠道吸收而产生的体液作用。,European Journal of Pharmacology

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新型浓缩核苷转运蛋白2抑制剂通过抑制嘌呤核苷的肠道吸收而产生的体液作用。
European Journal of Pharmacology ( IF 4.2 ) Pub Date : 2012-06-20 , DOI: 10.1016/j.ejphar.2012.06.015
Masahiro Hiratochi ₁ , Kazuya Tatani , Kazuo Shimizu , Yu Kuramochi , Norihiko Kikuchi , Noboru Kamada , Fumiaki Itoh , Masayuki Isaji

Affiliation

我们已经开发了浓缩核苷转运蛋白2（CNT2）抑制剂作为通过抑制嘌呤的肠道吸收来改善高尿酸血症的新型药理方法。膳食嘌呤核苷通过在顶端膜中表达的CNT在小肠中吸收。在人类中，被黄嘌呤氧化酶将吸收的嘌呤核苷迅速降解为它们的最终终产物尿酸。基于人类碳纳米管在消化道组织中的表达谱，我们建立了一个可行的假设，即主要碳纳米管2有助于嘌呤核苷的肠道吸收。为了证实这种可能性，我们开发了CNT2抑制剂，发现（2R，3R，4S，5R）-2-（6-氨基-8-{[3'-（3-氨基丙氧基）-联苯-4-基甲基] -氨基} -9H-嘌呤-9-基）-5-羟甲基-四氢呋喃-3,4-二醇（KGO-2142）和1- [3-（5-{[1-（（2R，3R，4S，5R）-3,4-二羟基-5-羟甲基-四氢呋喃-2-基）-1H-苯并咪唑-2-基氨基]-甲基} -2-乙氧基苯氧基）丙基]-哌啶-4-羧酸酰胺（KGO-2173）具有抑制作用。这些CNT2抑制剂对通过人CNT2吸收肌苷具有有效的抑制活性，但它们在体外并未有效干扰通过人CNT1，CNT3或平衡核苷转运蛋白（ENTs）吸收核苷。口服施用KGO-2173和[（14）C]-肌苷后，KGO-2173显着降低了大鼠在6和24h时的放射性放射性排泄。由于日粮嘌呤核苷没有在体内利用，而是迅速排泄到尿中，因此尿中放射性的这种降低代表了KGO-2173对小肠中[[14] C]-肌苷吸收的抑制活性。KGO-2142几乎完全抑制了饮食性RNA引起的高尿酸血症以及cebus猴子中尿酸的尿排泄增加。这些新型的CNT2抑制剂KGO-2142和KGO-2173可能是治疗高尿酸血症的有用治疗选择。

"点击查看英文标题和摘要"

Hypouricemic effects of novel concentrative nucleoside transporter 2 inhibitors through suppressing intestinal absorption of purine nucleosides.

We have developed concentrative nucleoside transporter 2 (CNT2) inhibitors as a novel pharmacological approach for improving hyperuricemia by inhibiting intestinal absorption of purines. Dietary purine nucleosides are absorbed in the small intestines by CNTs expressed in the apical membrane. In humans, the absorbed purine nucleosides are rapidly degraded to their final end product, uric acid, by xanthine oxidase. Based on the expression profile of human CNTs in digestive tract tissues, we established a working hypothesis that mainly CNT2 contributes to the intestinal absorption of purine nucleosides. In order to confirm this possibility, we developed CNT2 inhibitors and found that (2R,3R,4S,5R)-2-(6-amino-8-{[3'-(3-aminopropoxy)-biphenyl-4-ylmethyl]-amino}-9H-purin-9-yl)-5-hydroxymethyl-tetrahydrofuran-3,4-diol (KGO-2142) and 1-[3-(5-{[1-((2R,3R,4S,5R)-3,4-dihydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl)-1H-benzimidazol-2-ylamino]-methyl}-2-ethoxyphenoxy)-propyl]-piperidine-4-carboxylic acid amide (KGO-2173) were inhibitory. These CNT2 inhibitors had potent inhibitory activity against inosine uptake via human CNT2, but they did not potently interfere with nucleoside uptake via human CNT1, CNT3 or equilibrative nucleoside transporters (ENTs) in vitro. After oral administration of KGO-2173 along with [(14)C]-inosine, KGO-2173 significantly decreased the urinary excretion of radioactivity at 6 and 24h in rats. Since dietary purine nucleosides are not utilized in the body and are excreted into the urine rapidly, this decrease in radioactivity in the urine represented the inhibitory activity of KGO-2173 toward the absorption of [(14)C]-inosine in the small intestines. KGO-2142 almost completely inhibited dietary RNA-induced hyperuricemia and the increase in urinary excretion of uric acid in cebus monkeys. These novel CNT2 inhibitors, KGO-2142 and KGO-2173, could be useful therapeutic options for the treatment of hyperuricemia.

更新日期：2019-11-01

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