Discovery and characterization of novel TRPML1 agonists

被引：2

作者：

Peng, Xiaowen ^{[1
]}

Holler, Christopher J. ^{[1
]}

Alves, Anna -Maria F. ^{[1
]}

Oliviera, Michelle G. ^{[1
]}

Speake, Michael ^{[2
]}

Pugliese, Angelo ^{[2
]}

Oskouei, Mina R. ^{[3
]}

de Freitas, Ivan D. ^{[3
]}

Chen, Angela Y. -P. ^{[1
]}

Gallegos, Richard ^{[1
]}

McTighe, Stephanie M. ^{[1
]}

Koenig, Gerhard ^{[1
]}

Hurst, Raymond S. ^{[1
]}

Blain, Jean-Francois ^{[1
]}

Lanter, James C. ^{[1
]}

Burnett, Duane A. ^{[1
]}

机构：

[1] Arkuda Therapeut, 200 Arsenal Yards Blvd Suite 220, Watertown, MA 02472 USA

[2] BioAscent Discovery Ltd, BoNess Rd, Motherwell ML1 5UH, Scotland

[3] Symeres Inc, Kerkenbos 1013, NL-6546 BB Nijmegen, Netherlands

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2024年 / 98卷

关键词：

TRPML1; activation; Agonist; Lysosomal storage disorders; Mucolipidosis type IV; Alzheimer 's disease (AD); Neurodegeneration; LYSOSOME; CLEARANCE; DISEASE;

D O I：

10.1016/j.bmcl.2023.129595

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页数：6

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