4RZ1: Renin In Complexed With (3s,4s)-4-({[4-methoxy-3-(3-methoxypropoxy) Benzoyl](propan-2-yl)amino}methyl)pyrrolidin-3-yl Benzylcarbamate Inhibitor

Inhibition of the aspartyl protease renin is considered as an efficient approach for treating hypertension. Lately, we described the discovery of a novel class of direct renin inhibitors which comprised a pyrrolidine scaffold (e.g., 2). Based on the X-ray structure of the lead compound 2 bound to renin we predicted that optimization of binding interactions to the prime site could offer an opportunity to further expand the scope of this chemotype. Pyrrolidine-based inhibitors were synthesized in which the prime site moieties are linked to the pyrrolidine core through an oxygen atom, resulting in an ether or a carbamate linker subseries. Especially the carbamate derivatives showed a pronounced increase in in vitro potency compared to 2. Here we report the structure-activity relationship of both subclasses and demonstrate blood pressure lowering effects for an advanced prototype in a hypertensive double-transgenic rat model after oral dosing.
PDB ID: 4RZ1Download
MMDB ID: 128069
PDB Deposition Date: 2014/12/18
Updated in MMDB: 2015/04
Experimental Method:
x-ray diffraction
Resolution: 2.6  Å
Source Organism:
Similar Structures:
Biological Unit for 4RZ1: monomeric; determined by author
Molecular Components in 4RZ1
Label Count Molecule
Protein (1 molecule)
Renin(Gene symbol: REN)
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB