Discovery of bisamide-heterocycles as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Dockendorff, Chris^1,2  Faloon, Patrick W.¹  Germain, Andrew¹  Yu, Miao³  Youngsaye, Willmen¹  Nag, Partha P.¹  Bennion, Melissa¹  Penman, Marsha³  Nieland, Thomas J. F.³  Dandapani, Sivaraman¹  Perez, Jose R.¹  Munoz, Benito¹  Palmer, Michelle A.¹  Schreiber, Stuart L.^1,4  Krieger, Monty³ 

[1] Broad Inst, Ctr Sci Therapeut, Cambridge Ctr 7, Cambridge, MA 02142 USA

[2] Marquette Univ, Dept Chem, Milwaukee, WI 53201 USA

[3] MIT, Dept Biol, Cambridge, MA 02139 USA

[4] MIT, Howard Hughes Med Inst, Broad Inst, Cambridge Ctr 7, Cambridge, MA 02142 USA

关键词: ML279;    SR-BI inhibitor;    HDL receptor;    Cholesterol transport;    HCV;   

DOI  :  10.1016/j.bmcl.2015.03.074

来源: Elsevier

【 摘 要 】

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)-stereo-chemistry 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. (C) 2015 The Authors. Published by Elsevier Ltd.

【 授权许可】

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