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CARDIOVASCULAR

The Prototypical Inhibitor of Cholesterol Esterification, Sah 58-035 [3-[Decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]propanamide], Is an Agonist of Estrogen Receptors

Institut National de la Santé et de la Recherche Médicale U-563, Département Innovation Thérapeutique et Oncologie Moléculaire/Centre de Physiopathologie de Toulouse Purpan, Toulouse, France (P.d.M., N.B., G.F., S.S.-P., M.P.); Institut Claudius Regaud, Toulouse, France (G.F., S.S.-P., M.P.); Université Paul Sabatier, Toulouse, France (G.F., S.S.-P., M.P.); Affichem, Toulouse, France (P.d.M.); and Institut National de la Santé et de la Recherche Médicale U-540, Endocrinologie Moléculaire et Cellulaire des Cancers, Montpellier, France (P.B.)

We have shown recently that estrogen receptor (ER) ligands share a diphenyl ethane pharmacophore with Sah 58-035 [3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]-propanamide], a prototypical inhibitor of the acyl-cholesterolacyl-transferase (ACAT), which enabled us to establish that ER ligands were potent inhibitors of ACAT and blocked the formation of foam cells. In the present study, we have tested whether this structural similarity means that Sah 58-035 is an ER modulator. We report that Sah 58-035 bound to ER and ER with an IC₅₀ of 2.9 and 3.1 µM, respectively. Docking studies using molecular modeling of Sah 58-035 with the X-ray structure of the ER showed that Sah 58-035 fits well into the ligand binding site known for 4-hydroxy-tamoxifen. Despite having high three-dimensional structural similarities with the pure antiestrogen ICI 164,384 [(N-n-butyl-N-methyl-11-[3,17-di-hydroxyestra-1,3, 5(10)-trien-7-yl]-undecanamide], we showed that Sah 58-035 is an agonist of ER for transcription and cellular proliferation. These data showed that Sah 58-035 was an estrogen receptor agonist and that the size and the chemical nature of the side chain were critical for agonist versus antagonist activity on ER. This new molecular mechanism of action for Sah 58-035 has to be taken into account in understanding better its pharmacological activities. Moreover, these data give new structural insights into the understanding of agonist versus antagonist activities of ER ligands and also for the conception of new drugs with a dual ACAT inhibition and ER modulation potential and their evaluation in different pathologies where both targets are involved, such as atherosclerosis, Alzheimer's disease, and cancer.

Address correspondence to: Dr. Marc Poirot, Institut National de la Santé et de la Recherche Médicale U 563, Unit on Metabolism, Oncogenesis, and Cell Differentiation, ITOM/CPTP, Institut Claudius Regaud, 20-24 rue du Pont Saint Pierre, 31052 Toulouse cedex, France. E-mail: Marc_Poirot{at}hotmail.com

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