title: Structure-based optimization of potent 4- and 6-azaindole-3-carboxamides as renin inhibitors.
abstract: The control of hypertension and associated cardiovascular risk factors is possible by selective inhibition of the aspartyl protease renin due to its unique position in the renin-angiotensin system. Starting from a previously disclosed series of potent and nonchiral indole-3-carboxamides, we further explored this motif by structure-based drug design guided by X-ray crystallography in combination with efficient parallel synthesis. This resulted in the discovery of 4- or 6-azaindole derivatives with remarkable potency for renin inhibition. The best compound from these series showed an IC(50) value of 1.3 nM.
authors.affiliation: Sanofi-Aventis, Deutschland GmbH, Chemical and Analytical Sciences, Building G878, D-65926 Frankfurt, Germany.
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: 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: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D012083:Renin / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D012083:Renin; D000092502:Renin Inhibitors