Synthesis and structure-activity relationships of N-(4-amino-2,6-diisopropylphenyl)-N'-(1,4-diarylpiperidine-4-yl)methylureas as anti-hyperlipidemic agents.
Based on 1,4-diarylpiperidine-4-methylureas, a new class of ACAT inhibitors, we examined in the study the SAR of a series of compounds prepared by replacing the substituent at the three aromatic parts. Introduction of long alkoxy group onto the phenyl moiety at the B-part was effective in improving both the inhibitory activity for ACAT and the up-regulatory activity for LDL-R expression. Particularly, 3-hydroxypropoxy group (43) on the phenyl moiety of B-part led to improved solubility, while keeping both biological activities. Compound 43 inhibited ACAT activity with an IC(50) value of 18 nM, which is superior to that of a known ACAT inhibitor, CI-1011. In addition, compound 43 revealed an LDL-R up-regulatory activity comparable to that of SMP-797. We therefore expect this compound to be a novel ACAT inhibitor.
Asano
Shigehiro
S
Dainippon Sumitomo Pharma Co Ltd, Osaka, Japan. shigehiro-asano@ds-pharma.co.jp
Ban
Hitoshi
H
Kino
Koichi
K
Ioriya
Katsuhisa
K
Muraoka
Masami
M
D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D000960:Hypolipidemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D015854:Up-Regulation / Q000187:drug effects
D000960:Hypolipidemic Agents; D010671:Phenylurea Compounds; D010880:Piperidines; D011973:Receptors, LDL; D002785:Sterol O-Acyltransferase