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

Hirokazu HASHIZUME; Hajime ITO; Kohji YAMADA; Hajime NAGASHIMA; Munefumi KANAO; Hiroshi TOMODA; Toshiaki SUNAZUKA; Hidetoshi KUMAGAI; Satoshi OMURA

doi:10.1248/cpb.42.512

Hirokazu HASHIZUME, Hajime ITO, Kohji YAMADA, Hajime NAGASHIMA, Munefumi KANAO, Hiroshi TOMODA, Toshiaki SUNAZUKA, Hidetoshi KUMAGAI, Satoshi OMURA

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Keywords: 3-hydroxy-3-methylglutaryl coenzyme A synthase, 1233A analog, inhibitor, cholesterol biosynthesis, 2-oxetanone, structure-activity relationship

JOURNAL FREE ACCESS

1994 Volume 42 Issue 3 Pages 512-520

DOI https://doi.org/10.1248/cpb.42.512

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Abstract

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-oxetanone (23) showed the highest HMG-CoA synthase inhibitory activity in vitro. The structure-activity relationship at the side chain is discussed.

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