Parallel synthesis of acylsemicarbazide libraries: preparation of potent cyclin dependent kinase (cdk) inhibitors.
Potent cyclin dependent kinase inhibitors were prepared using parallel synthesis methodology. Treating advanced intermediate 2 with a variety of hydrazides in DMSO at 80 degrees C for 30 min gave the desired acylsemicarbazides in good to excellent yield. Several compounds were active against cdk4/D1 and cdk2/E in the low nanomolar range. The SAR indicates a wide variety of substituents are tolerated at the acylsemicarbazide moiety.
Dupont Pharmaceuticals, PO Box 80336, Wilmington, DE 19880-0336, USA. david.nugiel@astrazeneca.com
David A
DA
Nugiel
Anup
A
Vidwans
Carolyn D
CD
Dzierba
D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D051357:Cyclin-Dependent Kinase 2; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000037:antagonists & inhibitors; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D012663:Semicarbazides / Q000138:chemical synthesis* / Q000494:pharmacology*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D012663:Semicarbazides; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases