3KM4

Optimization of Orally Bioavailable Alkyl Amine Renin Inhibitors

Summary for 3KM4

• Entry DOI: 10.2210/pdb3km4/pdb
• Related: 3D91 3GW5
• Descriptor: Renin, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, (3R)-3-[(1S)-4-(acetylamino)-1-(3-chlorophenyl)-1-hydroxybutyl]-N-{(1S)-2-cyclohexyl-1-[(methylamino)methyl]ethyl}piperidine-1-carboxamide, ... (5 entities in total)
• Functional Keywords: renin, aspartate protease, hypertension, renin expression, renin inhibitor, aspartyl protease, cleavage on pair of basic residues, disulfide bond, glycoprotein, hydrolase, protease, secreted, zymogen, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P00797
• Total number of polymer chains: 2
• Total formula weight: 76609.34

Authors

Wu, Z.,McKeever, B.M. (deposition date: 2009-11-09, release date: 2010-01-12, Last modification date: 2024-11-06)

Primary citation

Xu, Z.,Cacatian, S.,Yuan, J.,Simpson, R.D.,Jia, L.,Zhao, W.,Tice, C.M.,Flaherty, P.T.,Guo, J.,Ishchenko, A.,Singh, S.B.,Wu, Z.,McKeever, B.M.,Scott, B.B.,Bukhtiyarov, Y.,Berbaum, J.,Mason, J.,Panemangalore, R.,Cappiello, M.G.,Bentley, R.,Doe, C.P.,Harrison, R.K.,McGeehan, G.M.,Dillard, L.W.,Baldwin, J.J.,Claremon, D.A.
Optimization of orally bioavailable alkyl amine renin inhibitors.
Bioorg.Med.Chem.Lett., 20:694-699, 2010

PubMed Abstract: Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension.

PubMed: 19959358
DOI: 10.1016/j.bmcl.2009.11.066

Experimental method

X-RAY DIFFRACTION (1.9 Å)