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 l...

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Veröffentlicht in:Chemical & pharmaceutical bulletin 1994/10/15, Vol.42(10), pp.2097-2107
Hauptverfasser: HASHIZUME, Hirokazu, ITO, Hajime, MORIKAWA, Tadanori, KANAYA, Naoaki, NAGASHIMA, Hajime, USUI, Hiroyuki, TOMODA, Hiroshi, SUNAZUKA, Toshiaki, KUMAGAI, Hidetoshi, OMURA, Satoshi
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Sprache:eng
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Zusammenfassung: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.
ISSN:0009-2363
1347-5223
DOI:10.1248/cpb.42.2097