Discovery and optimization of a new class of potent and non-chiral indole-3-carboxamide-based renin inhibitors.
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 2nM.
Scheiper
Bodo
B
Sanofi-Aventis Deutschland GmbH, Chemical and Analytical Sciences, Building G878, D-65926 Frankfurt, Germany. Bodo.Scheiper@sanofi-aventis.com
Matter
Hans
H
Steinhagen
Henning
H
Stilz
Ulrich
U
Böcskei
Zsolt
Z
Fleury
Valérie
V
McCort
Gary
G
D018360:Crystallography, X-Ray; D015195:Drug Design; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D008958:Models, Molecular; D011487:Protein Conformation; D012083:Renin / Q000737:chemistry; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D004791:Enzyme Inhibitors; D007211:Indoles; D012083:Renin; D000092502:Renin Inhibitors