Masami Ohtsuka

Discovery of DF-461, a Potent Squalene Synthase Inhibitor

We report the development of a new trifluoromethyltriazolobenzoxazepine series of squalene synthase inhibitors. Structure-activity studies and pharmacokinetics optimization on this series led to the identification of compound 23 (DF-461), which exhibited potent squalene synthase inhibitory activity, high hepatic selectivity, excellent rat hepatic cholesterol synthesis inhibitory activity, and plasma lipid lowering efficacy in nonrodent repeated dose studies.

Discovery of novel tricyclic compounds as squalene synthase inhibitors

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.

Correction to “Discovery of DF-461, a PotentSqualene Synthase Inhibitor”.

According to the recent reconsideration and re-evaluation of every author’s contribution of this work, all of authors have reached the final conclusion that we should rearrange the order of the authors and remove Dr. Usui from the author list as observed below. “Masanori Ichikawa,* Masami Ohtsuka, Hitoshi Ohki, Masahiro Ota, Noriyasu Haginoya, Masao Itoh, Yoshihiro Shibata, Kazuyuki Sugita, Yutaka Ishigai, Koji Terayama, Akira Kanda, and Hiroyuki Usui” to “Masanori Ichikawa,* Masami Ohtsuka, Hitoshi Ohki, Masahiro Ota, Noriyasu Haginoya, Masao Itoh, Yoshihiro Shibata, Yutaka Ishigai, Koji Terayama, Akira Kanda, and Kazuyuki Sugita.” All of authors have already approved this correction. Dr. Usui, our supervisor, also authorized and approved it.