Synthesis and biological activity of new 3-hydroxy-3-methylglutaryl-CoA synthase inhibitors: 2-oxetanones with a side chain mimicking the extended structure of 1233A.
Structural analogs of 1233A, a microbial metabolite inhibiting 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) synthase, were designed and synthesized. The 2-oxetanone moiety was left intact. All analogs prepared were tested for inhibition of HMG-CoA synthase activity and sterol synthesis in mouse liver and for effect on serum triglyceride levels. Of these analogs, trans-4-[2-[3-(7-carboxy-2- naphthyl)phenyl]ethyl]-3-hydroxymethyl-2-oxetanone (4a) showed the highest inhibitory activity in vitro, and also had in vivo inhibitory activity without causing any increase in triglyceride level.
Hashizume
H
H
Fuji Chemical Industries, Ltd., Toyama, Japan.
Ito
H
H
Morikawa
T
T
Kanaya
N
N
Nagashima
H
H
Usui
H
H
Tomoda
H
H
Sunazuka
T
T
Kumagai
H
H
Omura
S
S
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D005231:Fatty Acids, Unsaturated / Q000737:chemistry* / Q000494:pharmacology; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects*; D051379:Mice; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood*
D000900:Anti-Bacterial Agents; D005231:Fatty Acids, Unsaturated; D007783:Lactones; D014280:Triglycerides; C054282:antibiotic 1233A; D006904:Hydroxymethylglutaryl-CoA Synthase