AI Article Synopsis
- Researchers identified a new series of 8-membered benzo-fused lactams that block lipid uptake from HDL by targeting the SR-BI receptor, using a high-throughput screening method.
- The compounds were derived from a previously created diversity-oriented synthesis library, and extensive structure-activity relationship studies were conducted to determine the significance of substituent orientation.
- Among the compounds, 2p showed the best performance with an average potency of 0.10μM and a solubility of 79μM, earning it the designation probe ML312.
Article Abstract
We report a new series of 8-membered benzo-fused lactams that inhibit cellular lipid uptake from HDL particles mediated by Scavenger Receptor, Class B, Type I (SR-BI). The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR), measuring the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is part of a previously reported diversity-oriented synthesis (DOS) library prepared via a build-couple-pair approach. Detailed structure-activity relationship (SAR) studies were performed with a selection of the original library, as well as additional analogs prepared via solution phase synthesis. These studies demonstrate that the orientation of the substituents on the aliphatic ring have a critical effect on activity. Additionally, a lipophilic group is required at the western end of the molecule, and a northern hydroxyl group and a southern sulfonamide substituent also proved to be optimal. Compound 2p was found to possess a superior combination of potency (av IC50=0.10μM) and solubility (79μM in PBS), and it was designated as probe ML312.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469080 | PMC |
| http://dx.doi.org/10.1016/j.bmcl.2015.03.073 | DOI Listing |
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