Discovery and characterization of novel TRPML1 agonists

  • Bioorg Med Chem Lett. 2024 Jan 15:98:129595. doi: 10.1016/j.bmcl.2023.129595.
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
  • 1. Arkuda Therapeutics, 200 Arsenal Yards Blvd Suite 220, Watertown, MA 02472, USA. Electronic address: [email protected].
  • 2. Arkuda Therapeutics, 200 Arsenal Yards Blvd Suite 220, Watertown, MA 02472, USA.
  • 3. BioAscent Discovery Ltd, Bo'Ness Rd, Chapelhall, Motherwell ML1 5UH, United Kingdom.
  • 4. Symeres Inc, Kerkenbos 1013, 6546 BB Nijmegen, the Netherlands.
PMID: 38141860 DOI: 10.1016/j.bmcl.2023.129595
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.