Lead Discovery and Optimization Research Laboratories i

Shinagawa-ku, Japan

Lead Discovery and Optimization Research Laboratories i

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.


Iio Y.,Lead Discovery and Optimization Research Laboratories i | Yamaoka M.,Daiichi Sankyo | Jin M.,Daiichi Sankyo | Nakamura Y.,Daiichi Sankyo | Nishi T.,Lead Discovery and Optimization Research Laboratories i
Tetrahedron Asymmetry | Year: 2011

Herein we report the asymmetric synthesis of α,α-disubstituted α-amino alcohol derivatives 22, 25 and 26, key intermediates of a novel immunomodulator, using Seebach's method. This synthetic method can be applied to the large scale synthesis of chiral sphingosine 1-phosphate-1 (S1P 1) receptor agonists, with significant improvements to the previously reported method with regard to the reaction temperature. © 2011 Elsevier Ltd. All rights reserved.

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