Bentley J

Clegg W

Curtin NJ

Endicott JA

Golding BT

Griffin RJ

Haggerty K

Hardcastle IR

Harrington RW

Marchetti F

Mesguiche V

Newell DR

Noble MEM

Parsons RJ

Pratt DJ

Sayle KL

Wang L

An efficient synthesis of 2-substituted O4-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 \ub1 0.1 and 0.8 \ub1 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. This journal is \ua9 The Royal Society of Chemistry

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Structure-based design of 2-arylamino-4-cyclohexylmethoxy-5-nitroso-6- aminopyrimidine inhibitors of cyclin-dependent kinase 2

Structure-based design of 2-arylamino-4-cyclohexylmethoxy-5-nitroso-6- aminopyrimidine inhibitors of cyclin-dependent kinase 2

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