Discovery of oxazoline enhancers of cellular progranulin release. (15th January 2023)

• Record Type: Journal Article
• Authors: Peng, Xiaowen; Lanter, James C.; Y.-P. Chen, Angela; Brand, Morgan A.; Wozniak, Mary K.; Hoekman, Steven; Longin, Ondřej; Regeling, Hendrik; Zonneveld, Wim; P. L. Bell, Roel; Koenig, Gerhard; Hurst, Raymond S.; Blain, Jean-François; Burnett, Duane A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 80(2023)
• Publication Date: 2023-01-15
• Subjects: Progranulin -- Frontotemporal dementia -- Oxazoline -- Neurodegeneration -- CNS; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.129048
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 .