title: Macrocyclic aminopyrimidines as multitarget CDK and VEGF-R inhibitors with potent antiproliferative activities.
abstract: X-ray structures from CDK2-aminopyrimidine inhibitor complexes led to the idea to stabilize the active conformation of aminopyrimidine inhibitors by incorporating the recognition site into a macrocyclic framework. A modular synthesis approach that relies on a new late-stage macrocyclization protocol that enables fast and efficient synthesis of macrocyclic aminopyrimidines was developed. A set of structurally diverse derivatives was prepared. Macrocyclic aminopyrimidines were shown to be multitarget inhibitors of CDK1/2 and VEGF-RTKs. In addition, potent antiproliferative activities toward various human tumor cells and a human tumor xenograft model were demonstrated.
authors.affiliation: Medicinal Chemistry, Research Center Europe, Schering AG, 13342 Berlin, Germany. ulrich.luecking@schering.de
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lücking
authors.forename: Gerhard
authors.initials: G
authors.lastname: Siemeister
authors.forename: Martina
authors.initials: M
authors.lastname: Schäfer
authors.forename: Hans
authors.initials: H
authors.lastname: Briem
authors.forename: Martin
authors.initials: M
authors.lastname: Krüger
authors.forename: Philip
authors.initials: P
authors.lastname: Lienau
authors.forename: Rolf
authors.initials: R
authors.lastname: Jautelat
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000588:Amines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D040262:Receptors, Vascular Endothelial Growth Factor; D018844:Cyclin-Dependent Kinases