Design, synthesis, docking studies, and evaluation of losartan derivatives with potential dual activity at angiotensine II type 1 receptor and Peroxisome Proliferator Activated Receptor gamma
Résumé
Hypertension, diabetes and metabolic syndrome are important risk factors for cardiovascular morbidity and mortality. Angiotensin II plays an important role in blood pressure regulation and angiotensin II type 1 receptors (AT1) blockers are widely used in the treatment of hypertension. Some, such as telmisartan, and at a lesser degree, losartan, also exhibit activity at the Peroxisome Proliferator Activated Receptor gamma (PPAR-gamma), a nuclear receptor involved in the control of glucose metabolism. This represents a new therapeutic approach for the treatment of hypertension and diabetes, which are often concomitant and difficult to treat by one-target molecules. In this context, instead of pharmacomodulations on telmisartan (already done by Mizuno et al.), we preferably choose to modify the structure of losartan, in order to build-up new PPAR-gamma/AT1 dual molecules. The losartan structure was linked to a 4'-hydroxy-5-benzilidenethizolidinedione moiety, which is found in many PPAR-gamma agonists. Many chemical modulations were done on the resulting molecule, in order to get structure-activity relationships to both targets. In parallel, we realized docking experiments, with the aim of predicting the activities of the compounds. The molecules were docked into the PPAR-gamma receptor by the Autodock software, using a set of various PPAR-gamma X-ray structures from the Protein Data Bank. In order to validate the method, we first applied this procedure for rosiglitazone, a well-known PPAR-gamma agonist. In vitro AT1 activity was evaluated by displacement of fluorescent angiotensin II in cells overexpressing AT1 receptors. In vivo AT1 antagonistic activity was evaluated in anesthetized normotensive Wistar rats via the blunted hypertensive response to acute angiotensin II (10-10 mol/kg; intravenously). In vitro PPAR-gamma activity was evaluated in MCF-7 cells by co-transfection of (PPRE)3-TK-Luc and hPPAR-gamma vectors. As a result, many molecules showed in vitro potency on AT1 or PPAR-gamma receptors. Furthermore, some exhibited strong in vivo antihypertensive activity.