Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 2, Pages 492-501Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm801157z
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- IMB Research Foundation
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Twenty-nine derivatives of berberine (1) or pseudoberberine (2) were designed, semisynthesized, and evaluated for their up-regulatory activity on the low-density-lipoprotein receptor (LDLR) expression. SAR analysis revealed that (i) the methylenedioxy group at the 2- and 3-position is an essential element to keep the activity, (ii) the 7-position quaternary ammonium and planar structure of the compound are activity-required, and (iii) addition of electron-donating groups at the 7- or 13-position reduced the activity. Of the compound I analogues, compound 2 exhibited an increased activity on LDLR expression compared to 1. In the hyperlipidemic rats, compound 2 (100 (mg/kg)/day) reduced blood CHO and LDL-c by 42.6% and 49.4%, respectively, more efficient than I did (p < 0.01 for both). The results were confirmed in the hyperlipidemic mice. LD50 of 2 in mice was over 5000 mg/kg (oral). We consider compound 2 a promising cholesterol-lowering drug candidate.
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