Faculty Collaboration Database

Discovery of bisamide-heterocycles as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake. Bioorg Med Chem Lett 2015 Jun 15;25(12):2594-8

Date

05/11/2015

Pubmed ID

25958245

Pubmed Central ID

PMC4469081

DOI

10.1016/j.bmcl.2015.03.074

Scopus ID

2-s2.0-84929994575 (requires institutional sign-in at Scopus site)   11 Citations

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.

Author List

Dockendorff C, Faloon PW, Germain A, Yu M, Youngsaye W, Nag PP, Bennion M, Penman M, Nieland TJ, Dandapani S, Perez JR, Munoz B, Palmer MA, Schreiber SL, Krieger M

Author

Christopher Dockendorff PhD Assistant Professor, Organic and Medicinal Chemistry in the Chemistry department at Marquette University

MESH terms used to index this publication - Major topics in bold

Alanine
Animals
CD36 Antigens
CHO Cells
Cricetinae
Cricetulus
Drug Evaluation, Preclinical
Furans
Heterocyclic Compounds
Lipoproteins, HDL
Protein Binding
Structure-Activity Relationship
Tetrazoles