title: Benzo-fused lactams from a diversity-oriented synthesis (DOS) library as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake.
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.
authors.affiliation: 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.
authors.forename: Chris
authors.initials: C
authors.lastname: Dockendorff
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Faloon
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Pu
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Johnston
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Bennion
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Marsha
authors.initials: M
authors.lastname: Penman
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Thomas J F
authors.initials: TJ
authors.lastname: Nieland
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Sivaraman
authors.initials: S
authors.lastname: Dandapani
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: José R
authors.initials: JR
authors.lastname: Perez
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Palmer
authors.affiliation: 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.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: krieger@MIT.edu.
authors.forename: Monty
authors.initials: M
authors.lastname: Krieger
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D007769:Lactams / Q000737:chemistry / Q000494:pharmacology*; D050356:Lipid Metabolism; D013329:Structure-Activity Relationship
chemical_list: D018955:CD36 Antigens; D007769:Lactams
keywords: Cholesterol transport; DOS macrocycle; HDL receptor; ML312; SR-BI inhibitor