New pyripyropene A derivatives, highly SOAT2-selective inhibitors, improve hypercholesterolemia and atherosclerosis in atherogenic mouse models.
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.
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.).
Taichi
T
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.).
Masaki
M
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.).
Tohru
T
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.).
Daisuke
D
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.).
Hiroaki
H
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.).
Matthew A
MA
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.).
Lawrence L
LL
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.).
Shun
S
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.) tomodah@pharm.kitasato-u.ac.jp.
Hiroshi
H
Tomoda
D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016466:CHO Cells; D002784:Cholesterol / Q000097:blood; D002788:Cholesterol Esters / Q000097:blood; D003412:Cricetulus; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D066292:Lipid Droplets / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011973:Receptors, LDL / Q000235:genetics; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000097587:Sterol O-Acyltransferase 2
D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D002784:Cholesterol; D002788:Cholesterol Esters; D008074:Lipoproteins; D011725:Pyridines; D011973:Receptors, LDL; D012717:Sesquiterpenes; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; C082792:pyripyropene A