Discovery of oxazoline enhancers of cellular progranulin release

Xiaowen Peng; James C Lanter; Angela Y-P Chen; Morgan A Brand; Mary K Wozniak; Steven Hoekman; Ondřej Longin; Hendrik Regeling; Wim Zonneveld; Roel P L Bell; Gerhard Koenig; Raymond S Hurst; Jean-François Blain; Duane A Burnett

doi:10.1016/j.bmcl.2022.129048

Discovery of oxazoline enhancers of cellular progranulin release

Bioorg Med Chem Lett. 2023 Jan 15:80:129048. doi: 10.1016/j.bmcl.2022.129048. Epub 2022 Nov 8.

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.

MeSH terms

Frontotemporal Dementia*
Humans
Intercellular Signaling Peptides and Proteins*
Progranulins

Substances

Progranulins
Intercellular Signaling Peptides and Proteins