Structure-based design of 2-arylamino-4-cyclohexylmethoxy-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinase 2.
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.
Marchetti
Francesco
F
Northern Institute for Cancer Research, School of Natural Sciences-Chemistry, Bedson Building, Newcastle University, Newcastle Upon Tyne, UKNE1 7RU.
Sayle
Kerry L
KL
Bentley
Johanne
J
Clegg
William
W
Curtin
Nicola J
NJ
Endicott
Jane A
JA
Golding
Bernard T
BT
Griffin
Roger J
RJ
Haggerty
Karen
K
Harrington
Ross W
RW
Mesguiche
Veronique
V
Newell
David R
DR
Noble
Martin E M
ME
Parsons
Rachel J
RJ
Pratt
David J
DJ
Wang
Lan Z
LZ
Hardcastle
Ian R
IR
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
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