| 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
|
| リソース情報 |
| ヒト・動物細胞 |
293T(RCB2202) |
