Discovery of oxazoline enhancers of cellular progranulin release

  • Bioorg Med Chem Lett. 2023 Jan 15;80:129048. doi: 10.1016/j.bmcl.2022.129048.
Xiaowen Peng  1 ,  James C Lanter  2 ,  Angela Y-P Chen  2 ,  Morgan A Brand  2 ,  Mary K Wozniak  2 ,  Steven Hoekman  3 ,  Ondřej Longin  3 ,  Hendrik Regeling  3 ,  Wim Zonneveld  3 ,  Roel P L Bell  3 ,  Gerhard Koenig  2 ,  Raymond S Hurst  2 ,  Jean-François Blain  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. Symeres, Kerkenbos 1013, 6546 BB Nijmegen, the Netherlands.
PMID: 36368496 DOI: 10.1016/j.bmcl.2022.129048
Abstract

Phenotypic screening of an annotated small molecule library and initial SAR studies identified compound 2 as a robust enhancer of progranulin secretion. Detailed SAR development on conformationally restricted carbamate isosteres led to the identification of compound 60 with a 3-fold improvement in BV-2 potency and a 9-fold decrease in hERG inhibition over compound 2, substantially improving this important margin of safety relative to compound 2.

Keywords
CNS; Frontotemporal dementia; Neurodegeneration; Oxazoline; Progranulin.
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