AI Article Synopsis
- The study focused on screening a small molecule library to find compounds that boost progranulin secretion, highlighting compound 2 as a key enhancer.
- Further structure-activity relationship (SAR) studies on modified carbamate compounds led to the discovery of compound 60.
- Compound 60 showed a significant increase in effectiveness with three times the potency in BV-2 cells and a ninefold reduction in hERG inhibition, suggesting a safer profile compared to compound 2.
Article 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.
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| http://dx.doi.org/10.1016/j.bmcl.2022.129048 | DOI Listing |
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