Novel 1,4-diarylpiperidine-4-methylureas as anti-hyperlipidemic agents: dual effectors on acyl-CoA:cholesterol O-acyltransferase and low-density lipoprotein receptor expression.
A family of 1,4-diarylpiperidine-4-methylureas were designed and synthesized as novel dual effectors on ACAT and LDL receptor expression. We examined SAR of the synthesized compounds focusing on substitution at the three aromatic parts of the starting compound 1 and succeeded in identifying essential substituents for inhibition of ACAT and up-regulation of hepatic LDL receptor expression. Especially, we found that compound 12f, which can easily be prepared, has biological properties comparable to those of SMP-797, a promising ACAT inhibitor. In addition, the in vitro effects of 12f on lipid metabolism were substantially superior to those of a known ACAT inhibitor, Avasimibe.
Asano
Shigehiro
S
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
Kino
Kouichi
K
Ioriya
Katsuhisa
K
Muraoka
Masami
M
D020650:Combinatorial Chemistry Techniques; D006801:Humans; D008782:Methylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011973:Receptors, LDL / Q000187:drug effects*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000187:drug effects*; D013329:Structure-Activity Relationship
D008782:Methylurea Compounds; D009287:Naphthyridines; D010880:Piperidines; D011973:Receptors, LDL; C508738:SMP-797; D002785:Sterol O-Acyltransferase