Markwalder, Jay A. published the artcileSynthesis and Biological Evaluation of 1-Aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one Inhibitors of Cyclin-Dependent Kinases, Application In Synthesis of 1869-22-3, the publication is Journal of Medicinal Chemistry (2004), 47(24), 5894-5911, database is CAplus and MEDLINE.
Using a high-throughput screening strategy, a series of 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-ones I [R1 = 2-ClC6H4, 2-Cl-6-FC6H3, 2,4,6-Cl3C6H2, etc.; R2 = Et, MeS, F3C, HOCH2, etc.; R3 = H, Me, cyclopropyl, MeO2C, 2-furyl, 3,4-(MeO)2C6H4, PhCH2, etc.] was identified that inhibit the cyclin-dependent kinase (CDK) 4/cyclin D1 complex-mediated phosphorylation of a protein substrate with IC50s in the low micromolar range. On the basis of preliminary structure-activity relationships (SAR), a model was proposed in which these inhibitors occupy the ATP-binding site of the enzyme, forming critical hydrogen bonds to the same residue (Val96) to which the amino group in ATP is presumed to bind. X-Ray diffraction studies on I [R1 = 2,4,6-Cl3C6H2; R2 = Et; R3 = 3,4-(HO)2C6H3CH2] bound to CDK2 support this binding mode. Iterative cycles of synthesis and screening lead to a novel series of potent, CDK2-selective 6-(arylmethyl)pyrazolopyrimidinones. Placement of a hydrogen-bond donor in the meta-position on the 6-arylmethyl group resulted in ∼100-fold increases in CDK4 affinity, giving ligands that were equipotent inhibitors of CDK4 and CDK2. These compounds exhibit antiproliferative effects in the NCI HCT116 and other cell lines. The potency of these antiproliferative effects is enhanced in anilide derivatives and translates into tumor growth inhibition in a mouse xenograft model.
Journal of Medicinal Chemistry published new progress about 1869-22-3. 1869-22-3 belongs to chlorides-buliding-blocks, auxiliary class Trifluoromethyl,Fluoride,Chloride,Hydrazine,Amine,Benzene, name is 1-(2-Chloro-5-(trifluoromethyl)phenyl)hydrazine, and the molecular formula is C7H6ClF3N2, Application In Synthesis of 1869-22-3.
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