Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor

  • ACS Med Chem Lett. 2012 Aug 18;3(9):754-8. doi: 10.1021/ml300168e.
Yuji Nakamura  1 ,  Teppei Fujimoto  1 ,  Yasuyuki Ogawa  1 ,  Chie Sugita  1 ,  Shojiro Miyazaki  1 ,  Kazuhiko Tamaki  1 ,  Mizuki Takahashi  1 ,  Yumi Matsui  1 ,  Takahiro Nagayama  1 ,  Kenichi Manabe  1 ,  Makoto Mizuno  1 ,  Noriko Masubuchi  1 ,  Katsuyoshi Chiba  1 ,  Takahide Nishi  1
Affiliations
  • 1. Lead Discovery & Optimization Research Laboratories I, Lead Discovery & Optimization Research Laboratories II, Cardiovascular-Metabolics Research Laboratories, Biological Research Laboratories, Drug Metabolism & Pharmacokinetics Research Laboratories, and Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
PMID: 24900544 DOI: 10.1021/ml300168e
Abstract

A novel orally bioavailable Renin Inhibitor, DS-8108b (5), showing potent Renin inhibitory activity and excellent in vivo efficacy is described. We report herein the synthesis and pharmacological effects of 5 including Renin inhibitory activity in vitro, suppressive effects of ex vivo plasma Renin activity (PRA) in cynomolgus monkey, pharmacokinetic data, and blood pressure-lowering effects in an animal model. Compound 5 demonstrated inhibitory activities toward human Renin (IC50 = 0.9 nM) and human and monkey PRA (IC50 = 1.9 and 6.3 nM, respectively). Oral administration of single doses of 3 and 10 mg/kg of 5 in cynomolgus monkey on pretreatment with furosemide led to dose-dependent significant reductions in ex vivo PRA and sustained lowering of mean arterial blood pressure for more than 12 h.

Keywords
4-aminoadamantan-1-ol; hypertension; plasma renin activity; renin inhibitor.
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