2. Academic Validation
  3. Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor

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

Affiliation

  • 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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