Discovery and characterization of novel TRPML1 agonists,Bioorganic & Medicinal Chemistry Letters

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Discovery and characterization of novel TRPML1 agonists
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2023-12-22 , DOI: 10.1016/j.bmcl.2023.129595
Xiaowen Peng ₁ , Christopher J Holler ₁ , Anna-Maria F Alves ₁ , Michelle G Oliviera ₁ , Michael Speake ₂ , Angelo Pugliese ₂ , Mina R Oskouei ₃ , Ivan D de Freitas ₃ , Angela Y-P Chen ₁ , Richard Gallegos ₁ , Stephanie M McTighe ₁ , Gerhard Koenig ₁ , Raymond S Hurst ₁ , Jean-François Blain ₁ , James C Lanter ₁ , Duane A Burnett ₁

Affiliation

Screening a library of >100,000 compounds identified the substituted tetrazole compound 1 as a selective TRPML1 agonist. Both enantiomers of compound 1 were separated and profiled in vitro and in vivo. Their selectivity, ready availability and CNS penetration should enable them to serve as the tool compounds of choice in future TRPML1 channel activation studies. SAR studies on conformationally locked macrocyclic analogs further improved the TRPML1 agonist potency while retaining the selectivity.

中文翻译：

新型 TRPML1 激动剂的发现和表征

通过筛选 >100,000 个化合物的文库，鉴定出取代的四唑化合物 1 作为选择性 TRPML1 激动剂。化合物 1 的两种对映体均在体外和体内进行了分离和分析。它们的选择性、现成可用性和中枢神经系统渗透性应该使它们能够作为未来 TRPML1 通道激活研究的首选工具化合物。对构象锁定大环类似物的 SAR 研究进一步提高了 TRPML1 激动剂的效力，同时保留了选择性。

更新日期：2023-12-22

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