A novel class of antihyperlipidemic agents with low density lipoprotein receptor up-regulation via the adaptor protein autosomal recessive hypercholesterolemia.
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; EC(25) = 0.047 microM). Compound 39 showed no ACAT inhibitory activity even at 1 microM. 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.
Asano
Shigehiro
S
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan. shigehiro-asano@ds-pharma.co.jp
Ban
Hitoshi
H
Tsuboya
Norie
N
Uno
Shinsaku
S
Kino
Kouichi
K
Ioriya
Katsuhisa
K
Kitano
Masafumi
M
Ueno
Yoshihide
Y
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D008078:Cholesterol, LDL / Q000097:blood; D006224:Cricetinae; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D034622:RNA Interference; D011973:Receptors, LDL / Q000096:biosynthesis*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation
C549344:2,6-diisopropylphenyl ((4-(3-methoxyphenyl)-1-pyrimidin-2-ylpiperidin-4-yl)carbonyl)sulfamate; D048868:Adaptor Proteins, Signal Transducing; D008078:Cholesterol, LDL; D000960:Hypolipidemic Agents; C469745:LDLRAP1 protein, human; D011743:Pyrimidines; D011973:Receptors, LDL; D013451:Sulfonic Acids; D014280:Triglycerides; D002785:Sterol O-Acyltransferase