Referenced in: none

Automatically associated channels: Kv11.1

Title: The discovery of AZD5597, a potent imidazole pyrimidine amide CDK inhibitor suitable for intravenous dosing.

Authors: Clifford D Jones, David M Andrews, Andrew J Barker, Kevin Blades, Paula Daunt, Simon East, Catherine Geh, Mark A Graham, Keith M Johnson, Sarah A Loddick, Heather M McFarland, Alexandra McGregor, Louise Moss, David A Rudge, Peter B Simpson, Michael L Swain, Kin Y Tam, Julie A Tucker, Mike Walker

Journal, date & volume: Bioorg. Med. Chem. Lett., 2008 Dec 15 , 18, 6369-73

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/18996007

Abstract
The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK) inhibitors is described. Optimisation of inhibitory potency against multiple CDK's (1, 2 and 9) resulted in imidazole pyrimidine amides with potent in vitro anti-proliferative effects against a range of cancer cell lines. Excellent physiochemical properties and large margins against inhibition of CYP isoforms and the hERG ion channel were achieved by modification of lipophilicity and amine basicity. A candidate with disease model activity in human cancer cell line xenografts and with suitable physiochemical and pharmacokinetic profiles for intravenous (i.v.) dosing was selected for further development as AZD5597.