PDBsum entry 3vuc

Hydrolase/hydrolase inhibitor

PDB id: 3vuc

Contents

Protein chain

340 a.a.

Ligands

NAG ×2

HHE ×2

Waters ×212

PDB id:

3vuc

Name:

Hydrolase/hydrolase inhibitor

Title:

Human renin in complex with compound 5

Structure:

Renin. Chain: a, b. Synonym: angiotensinogenase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ren. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: 293f.

Resolution:

2.60Å R-factor: 0.190 R-free: 0.243

Authors:

M.Takahashi,Y.Matsui,H.Hanzawa

Key ref:

Y.Nakamura et al. (2012). Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor. ACS Med Chem Lett, 3, 754-758. PubMed id: 24900544 DOI: 10.1021/ml300168e

Date:

26-Jun-12 Release date: 15-May-13

Protein chains

P00797  (RENI_HUMAN) -  Renin from Homo sapiens

Seq: 406 a.a.

Struc: 340 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.23.15 - renin.
• Reaction: Cleaves Leu-|- bond in angiotensinogen to generate angiotensin I.

DOI no: 10.1021/ml300168e

ACS Med Chem Lett 3:754-758 (2012)

PubMed id: 24900544

Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor.

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.

ABSTRACT

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.