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Research ArticleDrug Discovery and Translational Medicine

New Pyripyropene A Derivatives, Highly SOAT2-Selective Inhibitors, Improve Hypercholesterolemia and Atherosclerosis in Atherogenic Mouse Models

Taichi Ohshiro, Masaki Ohtawa, Tohru Nagamitsu, Daisuke Matsuda, Hiroaki Yagyu, Matthew A. Davis, Lawrence L. Rudel, Shun Ishibashi and Hiroshi Tomoda
Journal of Pharmacology and Experimental Therapeutics November 2015, 355 (2) 297-307; DOI: https://doi.org/10.1124/jpet.115.227348
Taichi Ohshiro
Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan (T.O., M.O., T.N., D.M., H.T.); Department of Medicine, Jichi Medical University, Tochigi, Japan (T.O., H.Y., S.I.); and Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (T.O., M.A.D., L.L.R.)
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Masaki Ohtawa
Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan (T.O., M.O., T.N., D.M., H.T.); Department of Medicine, Jichi Medical University, Tochigi, Japan (T.O., H.Y., S.I.); and Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (T.O., M.A.D., L.L.R.)
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Tohru Nagamitsu
Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan (T.O., M.O., T.N., D.M., H.T.); Department of Medicine, Jichi Medical University, Tochigi, Japan (T.O., H.Y., S.I.); and Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (T.O., M.A.D., L.L.R.)
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Daisuke Matsuda
Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan (T.O., M.O., T.N., D.M., H.T.); Department of Medicine, Jichi Medical University, Tochigi, Japan (T.O., H.Y., S.I.); and Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (T.O., M.A.D., L.L.R.)
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Hiroaki Yagyu
Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan (T.O., M.O., T.N., D.M., H.T.); Department of Medicine, Jichi Medical University, Tochigi, Japan (T.O., H.Y., S.I.); and Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (T.O., M.A.D., L.L.R.)
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Matthew A. Davis
Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan (T.O., M.O., T.N., D.M., H.T.); Department of Medicine, Jichi Medical University, Tochigi, Japan (T.O., H.Y., S.I.); and Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (T.O., M.A.D., L.L.R.)
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Lawrence L. Rudel
Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan (T.O., M.O., T.N., D.M., H.T.); Department of Medicine, Jichi Medical University, Tochigi, Japan (T.O., H.Y., S.I.); and Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (T.O., M.A.D., L.L.R.)
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Shun Ishibashi
Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan (T.O., M.O., T.N., D.M., H.T.); Department of Medicine, Jichi Medical University, Tochigi, Japan (T.O., H.Y., S.I.); and Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (T.O., M.A.D., L.L.R.)
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Hiroshi Tomoda
Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan (T.O., M.O., T.N., D.M., H.T.); Department of Medicine, Jichi Medical University, Tochigi, Japan (T.O., H.Y., S.I.); and Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (T.O., M.A.D., L.L.R.)
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Abstract

Sterol O-acyltransferase 2 (SOAT2; also known as ACAT2) is considered as a new therapeutic target for the treatment or prevention of hypercholesterolemia and atherosclerosis. Fungal pyripyropene A (PPPA: 1,7,11-triacyl type), the first SOAT2-selective inhibitor, proved orally active in vivo using atherogenic mouse models. The purpose of the present study was to demonstrate that the PPPA derivatives (PRDs) prove more effective in the mouse models than PPPA. Among 196 semisynthetic PPPA derivatives, potent, SOAT2-selective, and stable PRDs were selected. In vivo antiatherosclerotic activity of selected PRDs was tested in apolipoprotein E knockout (Apoe−/−) mice or low-density lipoprotein receptor knockout (Ldlr−/−) mice fed a cholesterol-enriched diet (0.2% cholesterol and 21% fat) for 12 weeks. During the PRD treatments, no detrimental side effects were observed. Among three PRDs, Apoe−/− mice treated with PRD125 (1-,11-O-benzylidene type) at 1 mg/kg/day had significantly lower total plasma cholesterol concentration by 57.9 ± 9.3%; further, the ratio of cholesteryl oleate to cholesteryl linoleate in low-density lipoprotein was lower by 55.6 ± 7.5%, respectively. The hepatic cholesteryl ester levels and SOAT2 activity in the small intestines and livers of the PRD-treated mice were selectively lowered. The atherosclerotic lesion areas in the aortae of PRD125-treated mice were significantly lower at 62.2 ± 13.1%, respectively. Furthermore, both PRDs were also orally active in atherogenic Ldlr−/− mice. Among the PRDs tested, PRD125 was the most potent in both mouse models. These results suggest that SOAT2-selective inhibitors such as PRD125 have a high potential as poststatin agents for treatment and/or prevention in patients with atherosclerosis and hypercholesterolemia.

Footnotes

    • Received July 1, 2015.
    • Accepted August 28, 2015.
  • This work was supported by the Program for Promotion of Fundamental Studies in Health Sciences from the National Institute of Biomedical Innovation (to H.T.); by a grant-in-aid for Scientific Research (A) 26253009 from the Ministry of Education, Culture, Sports, Science and Technology (to H.T.); by a grant-in-aid from Japan Society for the Promotion of Science (JSPS) and their Postdoctoral Fellowship for Research Abroad. (to T.O.); and by the U.S. National Institutes of Health National Heart Lung and Blood Institute [Grant HL-49373 to L.L.R.].

  • dx.doi.org/10.1124/jpet.115.227348.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 355 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 355, Issue 2
1 Nov 2015
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Research ArticleDrug Discovery and Translational Medicine

New Pyripyropene A Derivatives Improve Atherosclerosis

Taichi Ohshiro, Masaki Ohtawa, Tohru Nagamitsu, Daisuke Matsuda, Hiroaki Yagyu, Matthew A. Davis, Lawrence L. Rudel, Shun Ishibashi and Hiroshi Tomoda
Journal of Pharmacology and Experimental Therapeutics November 1, 2015, 355 (2) 297-307; DOI: https://doi.org/10.1124/jpet.115.227348

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Research ArticleDrug Discovery and Translational Medicine

New Pyripyropene A Derivatives Improve Atherosclerosis

Taichi Ohshiro, Masaki Ohtawa, Tohru Nagamitsu, Daisuke Matsuda, Hiroaki Yagyu, Matthew A. Davis, Lawrence L. Rudel, Shun Ishibashi and Hiroshi Tomoda
Journal of Pharmacology and Experimental Therapeutics November 1, 2015, 355 (2) 297-307; DOI: https://doi.org/10.1124/jpet.115.227348
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