Synthesis and biological activity of new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase inhibitors: 2-oxetanones with a side chain mimicking the folded structure of 1233A.
To mimic the folded side chain conformation of 1233A (1), which is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase inhibitor, 1233A analogs with aromatic rings in the side chain were synthesized. The 2-oxetanone moiety was kept intact. Among 1233A and its synthetic analogs, trans-3-hydroxymethyl-4-[2-(7-methoxycarbonyl-1-naphthyl)ethyl]-2-oxe tanone (23) showed the highest HMG-CoA synthase inhibitory activity in vitro. The structure-activity relationship at the side chain is discussed.
Hashizume
H
H
Fuji Chemical Industries, Ltd., Toyama, Japan.
Ito
H
H
Yamada
K
K
Nagashima
H
H
Kanao
M
M
Tomoda
H
H
Sunazuka
T
T
Kumagai
H
H
Omura
S
S
D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis* / Q000494:pharmacology; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000037:antagonists & inhibitors*; D007783:Lactones / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011420:Propiolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000924:Anticholesteremic Agents; D005231:Fatty Acids, Unsaturated; D007783:Lactones; C054282:antibiotic 1233A; D011420:Propiolactone; D006904:Hydroxymethylglutaryl-CoA Synthase