Bioorganic & Medicinal Chemistry 2011-09-01

Discovery of atrop fixed alkoxy-aminobenzhydrol derivatives: novel, highly potent and orally efficacious squalene synthase inhibitors.

Masanori Ichikawa, Aki Yokomizo, Masao Itoh, Noriyasu Haginoya, Kazuyuki Sugita, Hiroyuki Usui, Koji Terayama, Akira Kanda

Index: Bioorg. Med. Chem. 19(17) , 5207-24, (2011)

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Abstract

We have recently reported the discovery of the new benzhydrol template, which has a highly potent inhibitory activity for squalene synthase, as typified by compound 1 (SSI IC(50)=0.85 nM). However, it was composed of a pair of easy rotatable atropisomers. In the effort to fix the isomerization, a highly potent alkoxy-aminobenzhydrol scaffold was developed. Some of these acquired compounds demonstrating strong cholesterol synthesis inhibitory activities in a rat hepatic cell. Moreover, two of the series compounds exhibited specific plasma lipid-lowering effects in in vivo animal models.Copyright © 2011 Elsevier Ltd. All rights reserved.