Synthesis and Modeling of Ezetimibe Analogues |
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Authors: | Mateo M. Salgado,Alejandro Manchado,Carlos T. Nieto,David Dí ez,Narciso M. Garrido |
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Affiliation: | Departamento de Química Orgánica, Universidad de Salamanca, 37008 Salamanca, Spain; (M.M.S.); (A.M.); (C.T.N.); (D.D.) |
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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. |
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Keywords: | ezetimibe, cholesterol, ligand study, pharmacophore, domino reaction, chiral amide addition, Baylis– Hillman, β -lactam |
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