title: Structure-based design and optimization of potent renin inhibitors on 5- or 7-azaindole-scaffolds.
abstract: The selective inhibition of the aspartyl protease renin is of high interest to control hypertension and associated cardiovascular risk factors. Following on preceding contributions, we report herein on the optimization of two series of azaindoles to arrive at potent and non-chiral renin inhibitors. The previously discovered azaindole scaffold was further explored by structure-based drug design in combination with parallel synthesis. This results in the identification of novel 5- or 7-azaindole derivatives with remarkable potency for renin inhibition. The best compounds on both series show IC(50) values between 3 and 8nM.
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Chemical and Analytical Sciences, Building G878, D-65926 Frankfurt, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Matter
authors.forename: Bodo
authors.initials: B
authors.lastname: Scheiper
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: D001372:Aza Compounds / 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*; D007211:Indoles / 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: D001372:Aza Compounds; D004791:Enzyme Inhibitors; D007211:Indoles; D012083:Renin; D000092502:Renin Inhibitors; C512290:5-azaindole; C023422:7-azaindole dimer