title: Discovery and optimization of a new class of potent and non-chiral indole-3-carboxamide-based renin inhibitors.
abstract: 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.
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Chemical and Analytical Sciences, Building G878, D-65926 Frankfurt, Germany. Bodo.Scheiper@sanofi-aventis.com
authors.forename: Bodo
authors.initials: B
authors.lastname: Scheiper
authors.forename: Hans
authors.initials: H
authors.lastname: Matter
authors.forename: Henning
authors.initials: H
authors.lastname: Steinhagen
authors.forename: Ulrich
authors.initials: U
authors.lastname: Stilz
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Böcskei
authors.forename: Valérie
authors.initials: V
authors.lastname: Fleury
authors.forename: Gary
authors.initials: G
authors.lastname: McCort
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D012083:Renin; D000092502:Renin Inhibitors