1. trans-3,4-Disubstituted pyrrolidines as inhibitors of the human aspartyl protease renin. Part II: prime site exploration using an oxygen linker.
- Author
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Sellner H, Cottens S, Cumin F, Ehrhardt C, Kosaka T, Lorthiois E, Ostermann N, Webb RL, Rigel DF, Wagner T, and Maibaum J
- Subjects
- Animals, Aspartic Acid Proteases metabolism, Binding Sites, Crystallography, X-Ray, Disease Models, Animal, Humans, Hydrogen Bonding, Hypertension drug therapy, Isomerism, Molecular Dynamics Simulation, Oxygen chemistry, Protease Inhibitors metabolism, Protease Inhibitors therapeutic use, Protein Binding, Protein Structure, Tertiary, Pyrrolidines chemical synthesis, Pyrrolidines metabolism, Rats, Rats, Sprague-Dawley, Renin metabolism, Structure-Activity Relationship, Aspartic Acid Proteases antagonists & inhibitors, Protease Inhibitors chemistry, Pyrrolidines chemistry, Renin antagonists & inhibitors
- 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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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