3G70

Design and Preparation of Potent, Non-Peptidic, Bioavailable Renin Inhibitors

Summary for 3G70

• Entry DOI: 10.2210/pdb3g70/pdb
• Related: 3G6Z 3g72
• Descriptor: Renin, (1R,5S)-7-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-N-cyclopropyl-N-(2,3-dichlorobenzyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxamide, DIMETHYL SULFOXIDE, ... (5 entities in total)
• Functional Keywords: human renin, aspartyl protease, cleavage on pair of basic residues, disease mutation, glycoprotein, hydrolase, membrane, protease, secreted, zymogen
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P00797
• Total number of polymer chains: 2
• Total formula weight: 76702.95

Authors

Bezencon, O.,Bur, D.,Prade, L.,Weller, T.,Boss, C.,Fischli, W. (deposition date: 2009-02-09, release date: 2009-06-30, Last modification date: 2024-11-06)

Primary citation

Bezencon, O.,Bur, D.,Weller, T.,Richard-Bildstein, S.,Remen, L.,Sifferlen, T.,Corminboeuf, O.,Grisostomi, C.,Boss, C.,Prade, L.,Delahaye, S.,Treiber, A.,Strickner, P.,Binkert, C.,Hess, P.,Steiner, B.,Fischli, W.
Design and Preparation of Potent, Nonpeptidic, Bioavailable Renin Inhibitors
J.Med.Chem., 52:3689-3702, 2009

PubMed Abstract: Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.

PubMed: 19358611
DOI: 10.1021/jm900022f

Experimental method

X-RAY DIFFRACTION (2 Å)