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PDBsum entry 3vuc
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Hydrolase/hydrolase inhibitor
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PDB id
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3vuc
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References listed in PDB file
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Key reference
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Title
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Discovery of ds-8108b, A novel orally bioavailable renin inhibitor.
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Authors
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Y.Nakamura,
T.Fujimoto,
Y.Ogawa,
C.Sugita,
S.Miyazaki,
K.Tamaki,
M.Takahashi,
Y.Matsui,
T.Nagayama,
K.Manabe,
M.Mizuno,
N.Masubuchi,
K.Chiba,
T.Nishi.
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Ref.
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ACS Med Chem Lett, 2012,
3,
754-758.
[DOI no: ]
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PubMed id
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Abstract
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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.
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