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

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

  • Bioorg Med Chem Lett. 2015;25(10):2100-5. doi: 10.1016/j.bmcl.2015.03.073.
Chris Dockendorff 1,  Patrick W Faloon 2,  Jun Pu 2,  Miao Yu 3,  Stephen Johnston 2,  Melissa Bennion 2,  Marsha Penman 3,  Thomas J F Nieland 3,  Sivaraman Dandapani 2,  José R Perez 2,  Benito Munoz 2,  Michelle A Palmer 2,  Stuart L Schreiber 4,  Monty Krieger 5
Affiliations

Affiliations

  • 1 Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA; Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI 53201-1881, USA. Electronic address: christopher.dockendorff@marquette.edu.
  • 2 Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
  • 3 Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
  • 4 Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
  • 5 Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: krieger@MIT.edu.
PMID: 25900219 DOI: 10.1016/j.bmcl.2015.03.073
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.

Keywords

Cholesterol transport; DOS macrocycle; HDL receptor; ML312; SR-BI inhibitor.

Figures