Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor
Year: 2012
Type: article
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.
Source: ACS Medicinal Chemistry Letters
DOI: 10.1021/ml300168e
Authors: 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
Institution: Daiichi-Sankyo (Japan)
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2079928697