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Bioorg Med Chem Lett DOI:10.1016/j.bmcl.2015.03.073

Benzo-fused lactams from a diversity-oriented synthesis (DOS) library as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake.

Publication TypeJournal Article
Year of Publication2015
AuthorsDockendorff, C, Faloon, PW, Pu, J, Yu, M, Johnston, S, Bennion, M, Penman, M, Nieland, TJF, Dandapani, S, Perez, JR, Munoz, B, Palmer, MA, Schreiber, SL, Krieger, M
JournalBioorg Med Chem Lett
Date Published2015
KeywordsAnimals, CD36 Antigens, Humans, Lactams, Lipid Metabolism, Structure-Activity Relationship

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.


Alternate JournalBioorg. Med. Chem. Lett.
PubMed ID25900219
PubMed Central IDPMC4469080
Grant ListP01 HL066105 / HL / NHLBI NIH HHS / United States
R01 HL052212 / HL / NHLBI NIH HHS / United States
U54 HG005032 / HG / NHGRI NIH HHS / United States