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

doi:10.7164/antibiotics.49.1133

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

Department of Humanities and Social Sciences

Research output: Contribution to journal › Article › peer-review

26 Citations (Scopus)

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 language	English
Pages (from-to)	1133-1148
Number of pages	16
Journal	Journal of Antibiotics
Volume	49
Issue number	11
DOIs	https://doi.org/10.7164/antibiotics.49.1133
Publication status	Published - 1996

ASJC Scopus subject areas

Pharmacology
Drug Discovery

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

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).",

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

year = "1996",

doi = "10.7164/antibiotics.49.1133",

language = "English",

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T1 - Chemical modification and structure-activity relationships of pyripyropenes. 1. Modification at the four hydroxyl groups

AU - Obata, Rika

AU - Sunazuka, Toshiaki

AU - Li, Zhuorong

AU - Tian, Zhiming

AU - Harigaya, Yoshihiro

AU - Tabata, Noriko

AU - Tomoda, Hiroshi

AU - Omura, Satoshi

PY - 1996

Y1 - 1996

N2 - 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).

AB - 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).

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

Abstract

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