title: Structure-based design of 2-arylamino-4-cyclohexylmethoxy-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinase 2.
abstract: An efficient synthesis of 2-substituted O(4)-cyclohexylmethyl-5-nitroso-6-aminopyrimidines from 6-amino-2-mercaptopyrimidin-4-ol has been developed and used to prepare a range of derivatives for evaluation as inhibitors of cyclin-dependent kinase 2 (CDK2). The structure-activity relationships (SARs) are similar to those observed for the corresponding O(6)-cyclohexylmethoxypurine series with the 2-arylsulfonamide and 2-arylcarboxamide derivatives showing excellent potency. Two compounds, 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2-hydroxyethyl)benzenesulfonamide (7q) and 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2,3-dihydroxypropyl)benzenesulfonamide (7s), were the most potent with IC50 values of 0.7 +/- 0.1 and 0.8 +/- 0.0 nM against CDK2, respectively. The SARs determined in this study are discussed with reference to the crystal structure of 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2,3-dihydroxypropyl)benzenesulfonamide (7j) bound to phosphorylated CDK2/cyclin A.
authors.affiliation: Northern Institute for Cancer Research, School of Natural Sciences-Chemistry, Bedson Building, Newcastle University, Newcastle Upon Tyne, UKNE1 7RU.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marchetti
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Sayle
authors.forename: Johanne
authors.initials: J
authors.lastname: Bentley
authors.forename: William
authors.initials: W
authors.lastname: Clegg
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.forename: Jane A
authors.initials: JA
authors.lastname: Endicott
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: Karen
authors.initials: K
authors.lastname: Haggerty
authors.forename: Ross W
authors.initials: RW
authors.lastname: Harrington
authors.forename: Veronique
authors.initials: V
authors.lastname: Mesguiche
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.forename: Martin E M
authors.initials: ME
authors.lastname: Noble
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Parsons
authors.forename: David J
authors.initials: DJ
authors.lastname: Pratt
authors.forename: Lan Z
authors.initials: LZ
authors.lastname: Wang
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hardcastle
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D011743:Pyrimidines / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D000096926:Benzenesulfonamides
chemical_list: D000255:Adenosine Triphosphate; D019925:Cyclin A; D051357:Cyclin-Dependent Kinase 2; D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C495894:CDK2 protein, human