4RZ1

RENIN IN COMPLEXED WITH (3S,4S)-4-({[4-methoxy-3-(3-methoxypropoxy)benzoyl](propan-2-yl)amino}methyl)pyrrolidin-3-yl benzylcarbamate INHIBITOR

Summary for 4RZ1

• Entry DOI: 10.2210/pdb4rz1/pdb
• Descriptor: Renin, 2-acetamido-2-deoxy-beta-D-glucopyranose, (3S,4S)-4-({[4-methoxy-3-(3-methoxypropoxy)benzoyl](propan-2-yl)amino}methyl)pyrrolidin-3-yl benzylcarbamate, ... (6 entities in total)
• Functional Keywords: hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens
• Cellular location: Secreted: P00797
• Total number of polymer chains: 2
• Total formula weight: 76256.01

Authors

Ostermann, N. (deposition date: 2014-12-18, release date: 2015-03-25, Last modification date: 2024-10-30)

Primary citation

Sellner, H.,Cottens, S.,Cumin, F.,Ehrhardt, C.,Kosaka, T.,Lorthiois, E.,Ostermann, N.,Webb, R.L.,Rigel, D.F.,Wagner, T.,Maibaum, J.
trans-3,4-Disubstituted pyrrolidines as inhibitors of the human aspartyl protease renin. Part II: Prime site exploration using an oxygen linker.
Bioorg.Med.Chem.Lett., 25:1787-1791, 2015

PubMed Abstract: 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.

PubMed: 25754490
DOI: 10.1016/j.bmcl.2015.02.040

Experimental method

X-RAY DIFFRACTION (2.6 Å)