Discovery of novel tricyclic compounds as squalene synthase inhibitors

作者：Ichikawa Masanori^*; Ohtsuka Masami; Ohki Hitoshi; Haginoya Noriyasu; Itoh Masao; Sugita Kazuyuki; Usui Hiroyuki; Suzuki Makoto; Terayama Koji; Kanda Akira

来源：Bioorganic & Medicinal Chemistry, 2012, 20(9): 3072-3093.

DOI：10.1016/j.bmc.2012.02.054

• Hypercholesterolemia
• Squalene synthase inhibitor
• Pyrrolobenzoxazepine
• Lipid-lowering effect

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.

• 出版日期2012-5-1