2. Academic Validation
  3. Effect of a new squalene synthase inhibitor on an ApoE-/- mouse model of atherosclerosis

Effect of a new squalene synthase inhibitor on an ApoE-/- mouse model of atherosclerosis

  • Bioorg Med Chem. 2023 Jul 15;90:117378. doi: 10.1016/j.bmc.2023.117378.
Alexios N Matralis 1,  Loukas Kaklamanis 2,  Despina Perrea 3,  Angeliki P Kourounakis 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece; Bio-innovation Institute, Biomedical Sciences Research Center "Alexander Fleming", Vari, Athens, Greece. Electronic address: [email protected].
  • 2 Onassis Cardiac Surgery Center, Department of Pathology, Athens, Greece.
  • 3 Laboratory of Experimental Surgery and Surgical Research "N.S. Christeas", National and Kapodistrian University of Athens, Medical School, Athens, Greece.
  • 4 Department of Medicinal Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece. Electronic address: [email protected].
PMID: 37336084 DOI: 10.1016/j.bmc.2023.117378
Abstract

Ηypercholesterolemia/hyperlipidemia in conjunction with oxidative stress and inflammatory processes contribute synergistically to the pathogenesis of atherosclerosis. We hereby evaluated the antiatherosclerotic effect of the multi-target derivative 4-methyl-2-(10H-phenothiazin-3-yl)morpholin-2-ol hydrobromide 1 in apoE-/- mice; compound 1 is a potent antihyperlipidemic agent acting through Squalene Synthase inhibition, while it has exhibited an outstanding antioxidant and anti-inflammatory activity in various experimental animal models. The new analogue was evaluated in terms of its antiatherosclerotic/antioxidant effect in the ApoE-/- transgenic mouse model. Its toxicity profile was also assessed by measuring the levels of four sensitive indicators of liver toxicity. Prolonged administration of 1 in ApoE-/- mice fed with a western-type (wt) diet efficiently reduced the aortic atheromatic lesions, an effect that took place through a Cholesterol lowering independent manner. In addition, 1 displayed a significant reduction not only of glucose but also of oxidative stress levels, while it did not cause any toxicity. To the best of our knowledge this is the first time that the antiatherosclerotic effect of a Squalene Synthase inhibitor is studied in this specific atherosclerosis mouse model. As a result, compound 1 may serve as a promising starting point towards developing new bioactive analogues against the onset and subsequent development of atherosclerosis.

Keywords

Antiatherosclerotic agents; Multi-target compounds; Squalene synthase inhibitors.

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