Bioorganic & Medicinal Chemistry 2011-03-15

Discovery of a new 2-aminobenzhydrol template for highly potent squalene synthase inhibitors.

Masanori Ichikawa, Aki Yokomizo, Masao Itoh, Hiroyuki Usui, Hironari Shimizu, Makoto Suzuki, Koji Terayama, Akira Kanda, Kazuyuki Sugita

Index: Bioorg. Med. Chem. 19 , 1930-1949, (2011)

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Abstract

To obtain small and efficient squalene synthase inhibitors, a flexible 2-aminobenzhydrol open form structure was designed and showed potent inhibitory activity comparable to 4,1-benzoxazepin compounds. Further chemical modification led to the discovery of a novel template with a strong squalene synthase inhibitory activity, and its basic structure-activity relationship was revealed. The X-ray crystallographic data of compound 12 bound to the active site of squalene synthase provided an important insight into the binding mode of this alternative template that formed 11-membered ring conformations with an intramolecular hydrogen bond.Copyright © 2011 Elsevier Ltd. All rights reserved.