論文 - 詳細
| RRC ID | 65402 |
|---|---|
| 著者 | Kobayashi JI, Hirasawa H, Fujimori Y, Nakanishi O, Kamada N, Ikeda T, Yamamoto A, Kanbe H. |
| タイトル | Identification of N-acyl-N-indanyl-α-phenylglycinamides as selective TRPM8 antagonists designed to mitigate the risk of adverse effects. |
| ジャーナル | Bioorg Med Chem |
| Abstract |
Transient receptor potential melastatin 8 (TRPM8), a temperature-sensitive ion channel responsible for detecting cold, is an attractive molecular target for the treatment of pain and other disorders. We have previously discovered a selective TRPM8 antagonist, KPR-2579, which inhibited bladder afferent hyperactivity induced by acetic acid instillation into the bladder. However, additional studies have revealed potential adverse effects with KPR-2579, such as the formation of a reactive metabolite, CYP3A4 induction, and convulsions. In this report, we describe the optimization of α-phenylglycinamide derivatives to mitigate the risk of these adverse effects. The optimal compound 13x exhibited potent inhibition against icilin-induced wet-dog shakes and cold-induced frequent voiding in rats, with a wide safety margin against the potential side effects. |
| 巻・号 | 30 |
| ページ | 115903 |
| 公開日 | 2021-1-15 |
| DOI | 10.1016/j.bmc.2020.115903 |
| PII | S0968-0896(20)30733-1 |
| PMID | 33333445 |
| MeSH | Administration, Oral Animals Behavior, Animal / drug effects Dogs Dose-Response Relationship, Drug Female Humans Molecular Structure Pyrimidinones Rats Rats, Sprague-Dawley Risk Factors Structure-Activity Relationship TRPM Cation Channels / antagonists & inhibitors* TRPM Cation Channels / metabolism |
| IF | 3.073 |
| 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 | 3 |
| 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 | 293T(RCB2202) |