Department of Medicinal Chemistry, School of Pharmacy, University of Athens, Athens, Greece.
J Med Chem. 2011 Aug 11;54(15):5583-91. doi: 10.1021/jm200763k. Epub 2011 Jul 7.
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.
动脉粥样硬化是一种多因素疾病，有多种机制参与其表现。为了解决这个问题，我们采用了一种策略，设计了一种单一的化学化合物，能够同时调节多个靶点。在此，我们介绍了新型苯并恶嗪和苯并噻嗪衍生物的开发，这些化合物能显著抑制体外微粒体脂质过氧化和 LDL 氧化以及鲨烯合酶活性（IC50为 5-16 μM）。此外，这些化合物在体内具有抗脂血和抗氧化作用，可使高脂血症大鼠的总胆固醇、LDL、甘油三酯和 MDA 水平降低 26-74%。最后，通过测定其在靶组织（血液/肝脏）中的体内浓度（长达 24 小时），表明化合物在低微摩尔范围内达到其靶标。这些新化合物似乎是一种有趣的多功能分子，可用于开发一种新型治疗动脉粥样硬化的疾病修饰剂的药效基团。
