title: Design of more potent squalene synthase inhibitors with multiple activities.
abstract: With the increasing realization that modulating a multiplicity of targets can be an asset in the treatment of multifactorial disorders, we hereby report the synthesis and evaluation of the first compounds in which antioxidant, anti-inflammatory as well as squalene synthase (SQS) inhibitory activities are combined by design, in a series of simple molecules, extending their potential range of activities against the multifactorial disease of atherosclerosis. The activity of the initially synthesized antihyperlipidemic morpholine derivatives (1-6), in which we combined several pharmacophore moieties, was evaluated in vitro (antioxidant, inhibition of SQS and lipoxygenase) and in vivo (anti-dyslipidemic and anti-inflammatory effect). We further compared the in vitro SQS inhibitory action of these derivatives with theoretically derived molecular interactions by performing an in silico docking study using the X-ray crystal structure of human SQS. Based on low energy preferred binding modes, we designed potentially more potent SQS ligands. We proceeded with synthesizing and evaluating these new structures (7-12) in vitro and in vivo, to show that the new derivatives were significantly more active than formerly developed congeners, both as SQS inhibitors (20-70-fold increase in activity) and antioxidants (4-30-fold increase in activity). A significant correlation between experimental activity [Log(1/IC(50))] and the corresponding binding free energy (ΔG(b)) of the docked compounds was shown. These results, taken together, show a promising alternative and novel approach for the design and development of multifunctional antiatherosclerosis agents.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, 15771 Athens, Greece. angeliki@pharm.uoa.gr
authors.forename: Angeliki P
authors.initials: AP
authors.lastname: Kourounakis
authors.forename: Alexios N
authors.initials: AN
authors.lastname: Matralis
authors.forename: Anastasios
authors.initials: A
authors.lastname: Nikitakis
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008084:Lipoxygenase / Q000737:chemistry / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D016859:Lipoxygenase Inhibitors; D009025:Morpholines; C037574:morpholine; D008084:Lipoxygenase; D013186:Farnesyl-Diphosphate Farnesyltransferase