Synthesis and evaluation of new designed multiple ligands directed towards both peroxisome proliferator-activated receptor-γ and angiotensin II type 1 receptor

• DOI: 10.1016/j.ejmech.2018.08.082
• Publication Date: 2018-08-31T13:21:08Z
• Authors: Maxime Meyer; Sébastien Foulquier; François Dupuis; Stéphane Flament; Linda Grimaud; Daniel Henrion; Isabelle Lartaud; Gérald Monard; Isabelle Grillier...; Michel Boisbrun
• Keywords: Male; 0301 basic medicine; PPAR-γ; AGONISTS; 4-THIAZOLIDINONE DERIVATIVES; [CHIM.THER]Chemical Sciences/Medicinal Chemistry; Ligands; HIGHLY EFFICIENT; Receptor, Angiotensin, Type 1; AT1; 03 medical and health sciences; ANTAGONISTS; Animals; Humans; Chromans; Rats, Wistar; Imidazole; lmidazole; METABOLIC SYNDROME; ANTIPROLIFERATIVE ACTIVITY; Imidazoles; Chromane; Triazoles; AT(1); DUAL ACTIVITY; 3. Good health; DRUG DISCOVERY; ALZHEIMERS-DISEASE; Molecular Docking Simulation; PPAR gamma; Designed multiple ligands; PPAR-gamma; Drug Design; MCF-7 Cells; Triazole; PPAR-GAMMA; Angiotensin II Type 1 Receptor Blockers

Because of the complex biological networks, many pathologic disorders fail to be treated with a molecule directed towards a single target. Thus, combination therapies are often necessary, but they have many drawbacks. An alternative consists in building molecules intended to interact with multiple targets, called designed multiple ligands. We followed such a strategy in order to treat metabolic syndrome, by setting up molecules directed towards both type 1 angiotensin II (AT1) receptor and peroxisome proliferator-activated receptor-γ (PPAR-γ). For this purpose, many molecules were prepared by merging both pharmacophores following three different strategies. Their ability to activate PPAR-γ and to block AT1 receptors were evaluated in vitro. This strategy led to the preparation of many new PPAR-γ activating and AT1 blocking molecules. Among them, some exhibited both activities, highlighting the convenience of this approach.