title: The discovery of AZD5597, a potent imidazole pyrimidine amide CDK inhibitor suitable for intravenous dosing.
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.
authors.affiliation: Cancer and Infection Research, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. cliff.jones@astrazeneca.com
authors.forename: Clifford D
authors.initials: CD
authors.lastname: Jones
authors.forename: David M
authors.initials: DM
authors.lastname: Andrews
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Barker
authors.forename: Kevin
authors.initials: K
authors.lastname: Blades
authors.forename: Paula
authors.initials: P
authors.lastname: Daunt
authors.forename: Simon
authors.initials: S
authors.lastname: East
authors.forename: Catherine
authors.initials: C
authors.lastname: Geh
authors.forename: Mark A
authors.initials: MA
authors.lastname: Graham
authors.forename: Keith M
authors.initials: KM
authors.lastname: Johnson
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Loddick
authors.forename: Heather M
authors.initials: HM
authors.lastname: McFarland
authors.forename: Alexandra
authors.initials: A
authors.lastname: McGregor
authors.forename: Louise
authors.initials: L
authors.lastname: Moss
authors.forename: David A
authors.initials: DA
authors.lastname: Rudge
authors.forename: Peter B
authors.initials: PB
authors.lastname: Simpson
authors.forename: Michael L
authors.initials: ML
authors.lastname: Swain
authors.forename: Kin Y
authors.initials: KY
authors.lastname: Tam
authors.forename: Julie A
authors.initials: JA
authors.lastname: Tucker
authors.forename: Mike
authors.initials: M
authors.lastname: Walker
mesh_terms: D000577:Amides / Q000737:chemistry*; D045744:Cell Line, Tumor; D002627:Chemistry, Physical / Q000379:methods; D018360:Crystallography, X-Ray; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007262:Infusions, Intravenous; D008956:Models, Chemical; D008968:Molecular Conformation; D009368:Neoplasm Transplantation; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C540146:AZD5597; D000577:Amides; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007093:Imidazoles; C000606913:KCNH2 protein, human; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines