title: Synthesis and biological activity of new 3-hydroxy-3-methylglutaryl-CoA synthase inhibitors: 2-oxetanones with a meta-substituent on the benzene ring in the side chain.
abstract: Isosteric side chain analogs of 3a were synthesized and tested for inhibitory activities towards 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase and upon cholesterol production in Hep G2 cells and in mouse liver. It became clear that the lipophilic substituent on the aromatic ring and the terminal hydrophilic group in the side chain were important in the enhancement of activity. 4-[2-(3-n-Hexyloxyphenyl)ethyl]-3-hydroxy-methyl-2-oxetanone (5a) showed equivalent inhibitory activity in vivo to that of 1233A.
authors.affiliation: Fuji Chemical Industries, Ltd., Toyama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Hashizume
authors.forename: H
authors.initials: H
authors.lastname: Ito
authors.forename: N
authors.initials: N
authors.lastname: Kanaya
authors.forename: H
authors.initials: H
authors.lastname: Nagashima
authors.forename: H
authors.initials: H
authors.lastname: Usui
authors.forename: R
authors.initials: R
authors.lastname: Oshima
authors.forename: M
authors.initials: M
authors.lastname: Kanao
authors.forename: H
authors.initials: H
authors.lastname: Tomoda
authors.forename: T
authors.initials: T
authors.lastname: Sunazuka
authors.forename: H
authors.initials: H
authors.lastname: Kumagai
mesh_terms: D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000037:antagonists & inhibitors*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000494:pharmacology; D011420:Propiolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood
chemical_list: C089062:4-(2-(3-n-hexyloxyphenyl)ethyl)-3-hydroxymethyl-2-oxetanone; D010647:Phenyl Ethers; D014280:Triglycerides; D011420:Propiolactone; D002784:Cholesterol; D006904:Hydroxymethylglutaryl-CoA Synthase