期刊
MOLECULES
卷 26, 期 11, 页码 -出版社
MDPI
DOI: 10.3390/molecules26113107
关键词
ezetimibe; cholesterol; ligand study; pharmacophore; domino reaction; chiral amide addition; Baylis-Hillman; beta-lactam
资金
- Junta de Castilla y Leon [SA076P20, UIC021]
- University of Salamanca
- FSE (European Social Fund)
- Universidad de Salamanca
The passage discusses the mechanism of action of ezetimibe and its analogues in lowering blood cholesterol levels, as well as a convenient synthesis method. The study demonstrates the preparation of compounds with full stereochemical control through a series of reactions and showcases pharmacophore study on drug ligands.
Ezetimibe is a well-known drug that lowers blood cholesterol levels by reducing its absorption in the small intestine when joining to Niemann-Pick C1-like protein (NPC1L1). A ligandbased study on ezetimibe analogues is reported, together with one-hit synthesis, highlighted in the study. A convenient asymmetric synthesis of (2S,3S)-N-alpha-(R)-methylbenzyl-3-methoxycarbonylethyl-4-methoxyphenyl beta-lactam is described starting from Baylis-Hillman adducts. The route involves a domino process: allylic acetate rearrangement, stereoselective Ireland-Claisen rearrangement and asymmetric Michael addition, which provides a delta-amino acid derivative with full stereochemical control. A subsequent inversion of ester and acid functionality paves the way to the lactam core after monodebenzylation and lactam formation. It also shows interesting results when it comes to a pharmacophore study based on ezetimibe as the main ligand in lowering blood cholesterol levels, revealing which substituents on the azetidine-2-one ring are more similar to the ezetimibe skeleton and will more likely bind to NPC1L1 than ezetimibe.
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