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

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• 作者：Yuji Nakamura ; Teppei Fujimoto ; Yasuyuki Ogawa ; Chie Sugita ; Shojiro Miyazaki ; Kazuhiko Tamaki ; Mizuki Takahashi ; Yumi Matsui ; Takahiro Nagayama ; Kenichi Manabe ; Makoto Mizuno ; Noriko Masubuchi ; Katsuyoshi Chiba ; Takahide Nishi
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：3
• 期：9
• 页码：754-758
• 全文大小：328K
• 年卷期：v.3,no.9(September 13, 2012)
• ISSN：1948-5875

文摘

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:

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