Lead Discovery and Optimization Research Laboratories II

Shinagawa-ku, Japan

Lead Discovery and Optimization Research Laboratories II

Shinagawa-ku, Japan
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Nakamura Y.,Lead Discovery and Optimization Research Laboratories i | Fujimoto T.,Lead Discovery and Optimization Research Laboratories i | Ogawa Y.,Lead Discovery and Optimization Research Laboratories i | Sugita C.,Lead Discovery and Optimization Research Laboratories i | And 10 more authors.
ACS Medicinal Chemistry Letters | Year: 2012

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. © 2012 American Chemical Society.


Mizukoshi Y.,Japan National Institute of Advanced Industrial Science and Technology | Abe A.,Japan National Institute of Advanced Industrial Science and Technology | Takizawa T.,Lead Discovery and Optimization Research Laboratories II | Hanzawa H.,Lead Discovery and Optimization Research Laboratories II | And 5 more authors.
Angewandte Chemie - International Edition | Year: 2012

Irradiation makes the difference: The relaxation-rate differences of individual ligand protons (HA, HB) between the experiment with (see picture, red) and that without (blue) saturation of the protons of the protein target reflect the proximity to the protein surface. Thus, the binding portions of ligand molecules could be identified using this "difference of inversion recovery rate with and without target irradiation" (DIRECTION) method. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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