Macrocyclic aminopyrimidines as multitarget CDK and VEGF-R inhibitors with potent antiproliferative activities.
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.
Lücking
Ulrich
U
Medicinal Chemistry, Research Center Europe, Schering AG, 13342 Berlin, Germany. ulrich.luecking@schering.de
Siemeister
Gerhard
G
Schäfer
Martina
M
Briem
Hans
H
Krüger
Martin
M
Lienau
Philip
P
Jautelat
Rolf
R
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
D000588:Amines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D040262:Receptors, Vascular Endothelial Growth Factor; D018844:Cyclin-Dependent Kinases