Evaluation of amides, carbamates, sulfonamides and ureas of 4-prop-2-ynylidenecycloalkylamine as potent, selective, and bioavailable negative allosteric modulators of metabotropic glutamate receptor 5.
JOURNAL OF MEDICINAL CHEMISTRY(2019)
摘要
Negative allosteric modulators (NAMs) of the metabotropic glutamate receptor 5 (mGlu(5)) hold great promise for the treatment of a variety of central nervous system disorders. We have recently reported that prop-2-ynylidenecycloalkylamine derivatives are potent and selective NAMs of the mGlu(5) receptor. In this work, we explored the amide, carbamate, sulfonamide, and urea derivatives of prop-2-ynylidenecycloalkylamine compounds with the aim of improving solubility and metabolic stability. In silico and experimental analyses were performed on the synthesized series of compounds to investigate structure activity relationships. Compounds 12, 32, and 49 of the carbamate, urea, and amide classes, respectively, showed the most suitable cytochrome inhibition and metabolic stability profiles. Among them, compound 12 showed excellent selectivity, solubility, and stability profiles as well as suitable in vitro and in vivo pharmacokinetic properties. It was highly absorbed in rats and dogs and was active in anxiety, neuropathic pain, and lower urinary tract models.
更多查看译文
关键词
metabotropic glutamate receptor,bioavailable negative allosteric modulators,sulfonamides
AI 理解论文
溯源树
样例
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要