Chemical modification and structure-activity relationships of pyripyropenes. 1. Modification at the four hydroxyl groups

Rika Obata, Toshiaki Sunazuka, Zhuorong Li, Zhiming Tian, Yoshihiro Harigaya, Noriko Tabata, Hiroshi Tomoda, Satoshi Omura

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Abstract

Four hydroxyl groups of pyripyropenes have been modified and evaluated for their ability to inhibit microsomal acyl-CoA: cholesterol acyltransferase (ACAT) activity in vitro and to lower cholesterol absorption in vivo in a cholesterol-fed hamster. 7-O-n-Valeryl derivative (8c) improved the in vitro ACAT inhibitory activity (IC50 = 13 nM) about 7 times better than pyripyropene A. Introduction of methanesulfonyl group at 11-hydroxyl group (17a) increased both in vitro activity(IC50 = 19 nM) and in vivo efficacy (ED50 = 10 mg/kg).

Original languageEnglish
Pages (from-to)1133-1148
Number of pages16
JournalJournal of Antibiotics
Volume49
Issue number11
DOIs
Publication statusPublished - 1996 Jan 1

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ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

Cite this

Obata, R., Sunazuka, T., Li, Z., Tian, Z., Harigaya, Y., Tabata, N., Tomoda, H., & Omura, S. (1996). Chemical modification and structure-activity relationships of pyripyropenes. 1. Modification at the four hydroxyl groups. Journal of Antibiotics, 49(11), 1133-1148. https://doi.org/10.7164/antibiotics.49.1133