title: Novel benzoxazine and benzothiazine derivatives as multifunctional antihyperlipidemic agents.
abstract: Atherosclerosis is a multifactorial disease with several mechanisms participating in its manifestation. To address this disorder, we applied a strategy involving the design of a single chemical compound able to simultaneously modulate more than one target. We hereby present the development of novel benzoxazine and benzothiazine derivatives that significantly inhibit in vitro microsomal lipid peroxidation and LDL oxidation as well as squalene synthase activity (IC(50) of 5-16 μM). Further, these compounds show antidyslipidemic and antioxidant properties in vivo, decreasing total cholesterol, LDL, triglyceride, and MDA levels of hyperlipidemic rats by 26-74%. Finally, by determination of their in vivo concentration (up to 24 h) in target tissues (blood/liver), it is shown that compounds reach their targets in the low micromolar range. The new compounds seem to be interesting multifunctional molecules for the development of a new pharmacophore for disease-modifying agents useful in the treatment of atherosclerosis.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Athens, Athens, Greece.
authors.forename: Alexios N
authors.initials: AN
authors.lastname: Matralis
authors.forename: Maria G
authors.initials: MG
authors.lastname: Katselou
authors.forename: Anastasios
authors.initials: A
authors.lastname: Nikitakis
authors.forename: Angeliki P
authors.initials: AP
authors.lastname: Kourounakis
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy*; D048588:Benzoxazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008078:Cholesterol, LDL / Q000737:chemistry / Q000187:drug effects; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D051381:Rats; D013843:Thiazines / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D048588:Benzoxazines; D008078:Cholesterol, LDL; D000960:Hypolipidemic Agents; D013843:Thiazines; D013186:Farnesyl-Diphosphate Farnesyltransferase