2. Academic Validation
  3. Discovery of oxazoline enhancers of cellular progranulin release

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

Affiliations

  • 1 Arkuda Therapeutics, 200 Arsenal Yards Blvd Suite 220, Watertown, MA 02472, USA. Electronic address: xpeng@arkudatx.com.
  • 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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