3vuc

Human renin in complex with compound 5

spinqualitylabelsall models 3vuc, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3vuc is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.6Å Ligands: HHE, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease RENI_HUMAN Defects in REN are a cause of renal tubular dysgenesis (RTD) [MIM:267430. RTD is an autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype). Defects in REN are the cause of familial juvenile hyperuricemic nephropathy type 2 (HNFJ2) [MIM:613092. It is a renal disease characterized by juvenile onset of hyperuricemia, slowly progressive renal failure and anemia. Function RENI_HUMAN Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney. Publication Abstract from PubMed 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. Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor.,Nakamura Y, Fujimoto T, Ogawa Y, Sugita C, Miyazaki S, Tamaki K, Takahashi M, Matsui Y, Nagayama T, Manabe K, Mizuno M, Masubuchi N, Chiba K, Nishi T ACS Med Chem Lett. 2012 Aug 18;3(9):754-8. doi: 10.1021/ml300168e. eCollection, 2012 Sep 13. PMID:24900544 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Renin

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