Discovery and optimization of a new class of potent and non-chiral indole-3-carboxamide-based renin inhibitors

Renin-Inhibitor (IC 50 = 0.002 μM). Selective inhibition of the aspartyl protease renin has gained attraction as an interesting approach to control hypertension and associated cardiovascular risk factors given its unique position in the renin–angiotensin system. Using a combination of high-throughpu...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-11, Vol.20 (21), p.6268-6272
Main Authors: Scheiper, Bodo, Matter, Hans, Steinhagen, Henning, Stilz, Ulrich, Böcskei, Zsolt, Fleury, Valérie, McCort, Gary
Format: Article
Language:English
Subjects:
Antihypertensive agents
Biological and medical sciences
Cardiovascular system
Crystallography, X-Ray
Drug Design
Drug Discovery
Drug Evaluation, Preclinical
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
Hypertension
Indole
Indoles - chemical synthesis
Indoles - pharmacology
Medical sciences
Models, Molecular
Pharmacology. Drug treatments
Protein Conformation
Renin - antagonists & inhibitors
Renin - chemistry
Renin inhibitors
Structure based design
Structure-Activity Relationship
X-ray crystallography
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Summary:Renin-Inhibitor (IC 50 = 0.002 μM). Selective inhibition of the aspartyl protease renin has gained attraction as an interesting approach to control hypertension and associated cardiovascular risk factors given its unique position in the renin–angiotensin system. Using a combination of high-throughput screening, parallel synthesis, X-ray crystallography and structure-based design, we identified and optimized a novel series of potent and non-chiral indole-3-carboxamides with remarkable potency for renin. The most potent compound 5k displays an IC 50 value of 2 nM.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.08.092