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Abe-Ohya R.,Cardiovascular Metabolics Research Laboratories | Ishikawa T.,Daiichi Sankyo | Shiozawa H.,Drug Metabolism and Pharmacokinetics Research Laboratories | Suda K.,Daiichi Sankyo | Nara F.,Cardiovascular Metabolics Research Laboratories
Journal of Receptors and Signal Transduction | Year: 2015

Ovarian cancer G-protein-coupled receptor 1 (OGR1) is a G-protein-coupled receptor (GPCR), which has previously been identified as a receptor for protons. It has been reported in this and previous studies that OGR1 expression was markedly up-regulated during osteoclast differentiation. We predicted the possibility of other molecules activating OGR1 in neutral pH, and that osteoblasts might release OGR1 agonistic molecules and activate OGR1 expressed in osteoclasts such as RANKL. We screened for cell supernatants and organ extracts and discovered OGR1 agonistic activity in ST-2 osteoblastic cell supernatants and pancreatic tissues. Finally, we partially purified and identified essential metals, Fe, Zn, Co, Ni and Mn, as novel OGR1 agonists. These OGR1 agonistic metals induce intracellular Gq-coupled inositol phosphate signals in OGR1-expressing cells and primary osteoclasts through OGR1. We also confirmed that these OGR1 agonistic metals activated OGR1 through the same residues which act with protons. Here, we demonstrate that metals, Fe, Zn, Co, Ni and Mn are the novel OGR1 agonists, which can singly activate OGR1 in neutral pH. © 2015 Daiichsankyo co. ltd. Source


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. Source

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