title: Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor.
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.
authors.affiliation: 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.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: 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.
authors.forename: Teppei
authors.initials: T
authors.lastname: Fujimoto
authors.affiliation: 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.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: 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.
authors.forename: Chie
authors.initials: C
authors.lastname: Sugita
authors.affiliation: 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.
authors.forename: Shojiro
authors.initials: S
authors.lastname: Miyazaki
authors.affiliation: 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.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tamaki
authors.affiliation: 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.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: 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.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Matsui
authors.affiliation: 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.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nagayama
authors.affiliation: 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.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Manabe
authors.affiliation: 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.
authors.forename: Makoto
authors.initials: M
authors.lastname: Mizuno
authors.affiliation: 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.
authors.forename: Noriko
authors.initials: N
authors.lastname: Masubuchi
authors.affiliation: 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.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: 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.
authors.forename: Takahide
authors.initials: T
authors.lastname: Nishi
keywords: 4-aminoadamantan-1-ol; hypertension; plasma renin activity; renin inhibitor