Bioorganic & Medicinal Chemistry 2012-05-01

Discovery of novel tricyclic compounds as squalene synthase inhibitors.

Masanori Ichikawa, Masami Ohtsuka, Hitoshi Ohki, Noriyasu Haginoya, Masao Itoh, Kazuyuki Sugita, Hiroyuki Usui, Makoto Suzuki, Koji Terayama, Akira Kanda

Index: Bioorg. Med. Chem. 20(9) , 3072-93, (2012)

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Abstract

In the present article, we have reported the design, synthesis, and identification of highly potent benzhydrol derivatives as squalene synthase inhibitors (compound 1). Unfortunately, the in vivo efficacies of the compounds were not enough for acquiring the clinical candidate. We continued our investigation to obtain a more in vivo efficacious template than the benzhydrol template. In our effort, we focused on a benzoxazepine ring and designed a new tricyclic scaffold by the incorporation of heterocycle into it. Prepared pyrrolobenzoxazepine derivatives showed further efficient in vitro and in vivo activities.Copyright © 2012 Elsevier Ltd. All rights reserved.