title: Discovery of bisamide-heterocycles as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake.
abstract: A new series of potent inhibitors of cellular lipid uptake from HDL particles mediated by scavenger receptor, class B, type I (SR-BI) was identified. The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR) that measured the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is characterized by a linear peptidomimetic scaffold with two adjacent amide groups, as well as an aryl-substituted heterocycle. Analogs of the initial hit were rapidly prepared via Ugi 4-component reaction, and select enantiopure compounds were prepared via a stepwise sequence. Structure-activity relationship (SAR) studies suggest an oxygenated arene is preferred at the western end of the molecule, as well as highly lipophilic substituents on the central and eastern nitrogens. Compound 5e, with (R)-stereochemistry at the central carbon, was designated as probe ML279. Mechanistic studies indicate that ML279 stabilizes the interaction of HDL particles with SR-BI, and its effect is reversible. It shows good potency (IC50=17 nM), is non-toxic, plasma stable, and has improved solubility over our alternative probe ML278.
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: Andrew
authors.initials: A
authors.lastname: Germain
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: Willmen
authors.initials: W
authors.lastname: Youngsaye
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Partha P
authors.initials: PP
authors.lastname: Nag
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: D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D018955:CD36 Antigens / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D005663:Furans / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000737:chemistry*; D008075:Lipoproteins, HDL / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D005663:Furans; D006571:Heterocyclic Compounds; D008075:Lipoproteins, HDL; C000605135:ML279 compound; D013777:Tetrazoles; C469777:bisamidine; D000409:Alanine
keywords: Cholesterol transport; HCV; HDL receptor; ML279; SR-BI inhibitor