論文 - 詳細
| RRC ID | 65998 |
|---|---|
| 著者 | Tatani K, Hiratochi M, Kikuchi N, Kuramochi Y, Watanabe S, Yamauchi Y, Itoh F, Isaji M, Shuto S. |
| タイトル | Identification of Adenine and Benzimidazole Nucleosides as Potent Human Concentrative Nucleoside Transporter 2 Inhibitors: Potential Treatment for Hyperuricemia and Gout. |
| ジャーナル | J Med Chem |
| Abstract |
To test the hypothesis that inhibitors of human concentrative nucleoside transporter 2 (hCNT2) suppress increases in serum urate levels derived from dietary purines, we previously identified adenosine derivative 1 as a potent hCNT2 inhibitor (IC50 = 0.64 μM), but further study was hampered due to its poor solubility. Here we describe the results of subsequent research to identify more soluble and more potent hCNT2 inhibitors, leading to the discovery of the benzimidazole nucleoside 22, which is the most potent hCNT2 inhibitor (IC50 = 0.062 μM) reported to date. Compound 22 significantly suppressed the increase in plasma uric acid levels after oral administration of purine nucleosides in rats. Because compound 22 was poorly absorbed orally in rats (F = 0.51%), its pharmacologic action was mostly limited to the gastrointestinal tract. These findings suggest that inhibition of hCNT2 in the gastrointestinal tract can be a promising approach for the treatment of hyperuricemia. |
| 巻・号 | 59(8) |
| ページ | 3719-31 |
| 公開日 | 2016-4-28 |
| DOI | 10.1021/acs.jmedchem.5b01884 |
| PMID | 27007871 |
| MeSH | Adenine / chemistry* Animals Benzimidazoles / chemistry* Gout / drug therapy* Humans Hyperuricemia / drug therapy* Male Membrane Transport Proteins / drug effects* Nucleosides / chemistry Nucleosides / pharmacokinetics Nucleosides / pharmacology* Nucleosides / therapeutic use Rats Rats, Sprague-Dawley |
| IF | 6.205 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 4 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | COS-7(RCB0539) |