A Novel Class of Antihyperlipidemic Agents with Low Density Lipoprotein Receptor Up-Regulation via the Adaptor Protein Autosomal Recessive Hypercholesterolemia

• Published in: Journal of medicinal chemistry Vol. 53; no. 8; pp. 3284 - 3295
• Main Authors: Asano, Shigehiro, Ban, Hitoshi, Tsuboya, Norie, Uno, Shinsaku, Kino, Kouichi, Ioriya, Katsuhisa, Kitano, Masafumi, Ueno, Yoshihide
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.04.2010; Amer Chemical Soc
• Subjects: Adaptor Proteins, Signal Transducing - physiology; Animals; Biological Availability; Cell Line, Tumor; Chemistry, Medicinal; Cholesterol, LDL - blood; Cricetinae; Humans; Hyperlipidemias - blood; Hyperlipidemias - drug therapy; Hypolipidemic Agents - chemical synthesis; Hypolipidemic Agents - pharmacokinetics; Hypolipidemic Agents - pharmacology; Life Sciences & Biomedicine; Male; Pharmacology & Pharmacy; Pyrimidines - chemical synthesis; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Receptors, LDL - biosynthesis; RNA Interference; Science & Technology; Sterol O-Acyltransferase - antagonists & inhibitors; Structure-Activity Relationship; Sulfonic Acids - chemical synthesis; Sulfonic Acids - pharmacokinetics; Sulfonic Acids - pharmacology; Triglycerides - blood; Up-Regulation; LDL RECEPTOR; LIVER; AFRICAN-GREEN MONKEYS; TOXICITY; CORONARY-HEART-DISEASE; ACYL-COA; ACAT INHIBITORS; PRIMARY PREVENTION; CHOLESTEROL ACYLTRANSFERASE INHIBITOR; ANTIATHEROSCLEROTIC AGENTS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm901909p

We have previously reported compound 2 as a inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase (ACAT) and up-regulator of the low density lipoprotein receptor (LDL-R) expression. In this study we focused on compound 2, a unique LDL-R up-regulator, and describe the discovery of a novel class of up-regulators of LDL-R. Replacement the methylene urea linker in compound 2 with an acylsulfonamide linker kept a potent LDL-R up-regulatory activity, and subsequent optimization work gave compound 39 as a highly potent LDL-R up-regulator (39; EC25 = 0.047 μM). Compound 39 showed no ACAT inhibitory activity even at 1 μM. The sodium salts of compound 39 reduced plasma total and LDL cholesterol levels in a dose-dependent manner in an experimental animal model of hyperlipidemia. Moreover, we revealed in this study using RNA interference that autosomal recessive hypercholesterolemia (ARH), an adaptor protein of LDL-R, is essential for compound 39 up-regulation of LDL-R expression.