Discovery of DF-461, a Potent Squalene Synthase Inhibitor

  • ACS Med Chem Lett. 2013 Sep 4;4(10):932-6. doi: 10.1021/ml400151c.
Masanori Ichikawa  1 ,  Masami Ohtsuka  1 ,  Hitoshi Ohki  1 ,  Masahiro Ota  1 ,  Noriyasu Haginoya  1 ,  Masao Itoh  1 ,  Yoshihiro Shibata  1 ,  Yutaka Ishigai  1 ,  Koji Terayama ,  Akira Kanda  1 ,  Kazuyuki Sugita  1
Affiliations
  • 1. R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
PMID: 24900587 DOI: 10.1021/ml400151c
Abstract

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.

Keywords
Squalene synthase; dyslipidemia; inhibitor; triazolobenzoxazepine.