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. 2024 Jan 15:98:129595.
doi: 10.1016/j.bmcl.2023.129595. Epub 2023 Dec 22.

Discovery and characterization of novel TRPML1 agonists

Xiaowen Peng  1 , Christopher J Holler  2 , Anna-Maria F Alves  2 , Michelle G Oliviera  2 , Michael Speake  3 , Angelo Pugliese  3 , Mina R Oskouei  4 , Ivan D de Freitas  4 , Angela Y-P Chen  2 , Richard Gallegos  2 , Stephanie M McTighe  2 , Gerhard Koenig  2 , Raymond S Hurst  2 , Jean-François Blain  2 , James C Lanter  2 , Duane A Burnett  2
Affiliations

Discovery and characterization of novel TRPML1 agonists

Xiaowen Peng et al. Bioorg Med Chem Lett. .

Abstract

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.

Keywords: Agonist; Alzheimer’s disease (AD); Lysosomal storage disorders; Mucolipidosis type IV; Neurodegeneration; TRPML1 activation.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: XP, CJH, AMFA, MGO, AYPC, RG, SMM, GK, RSH, JFB, JCL and DAB are currently, or were at the time the work was performed, employees of Arkuda Therapeutics with stock ownership. MS and AP are currently, or were at the time the work was performed, employees of BioAscent Discovery Ltd. MRO and IDF are currently, or were at the time the work was performed, employees of Symeres Inc. Both BioAscent Discovery Ltd and Symeres Inc have been business partners with Arkuda Therapeutics.

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