Synthesis and Modeling of Ezetimibe Analogues

Abstract

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 ligand-based study on ezetimibe analogues is reported, together with one-hit synthesis, highlighted in the study. A convenient asymmetric synthesis of (2S,3S)-N-α-(R)-methylbenzyl-3-methoxycarbonylethyl-4-methoxyphenyl β-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 δ-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.

Keywords: Baylis–Hillman; chiral amide addition; cholesterol; domino reaction; ezetimibe; ligand study; pharmacophore; β-lactam.

Scheme 1

Cyclopentane derivatives obtained from octadiendioates by domino reactions.

Scheme 2

Retrosynthesis of 2,3-disubstituted and 2,3,6-trisubstituted piperidines, as well as Ezetimibe analogue 1.

Scheme 3

Synthetic route towards the synthesis of Ezetimibe analogue 1.

Figure 1

The structural elements necessary for the activity.

Figure 2

Representation of the structural overlap of Ezetimibe (red) and L1 (green).