4-(Phenylaminomethylene)isoquinoline-1,3(2 H ,4 H )-diones as Potent and Selective Inhibitors of the Cyclin-Dependent Kinase 4 (CDK4)
Wyeth Research, 401 N Middletown Road, Pearl River, NY 10965, USA.Journal of Medicinal Chemistry (Impact Factor: 5.45). 07/2008; 51(12):3507-25. DOI: 10.1021/jm800072z
The cyclin-dependent kinases (CDKs), as complexes with their respective partners, the cyclins, are critical regulators of cell cycle progression. Because aberrant regulations of CDK4/cyclin D1 lead to uncontrolled cell proliferation, a hallmark of cancer, small-molecule inhibitors of CDK4/cyclin D1 are attractive as prospective antitumor agents. The series of 4-(phenylaminomethylene)isoquinoline-1,3(2H,4H)-dione derivatives reported here represents a novel class of potent inhibitors that selectively inhibit CDK4 over CDK2 and CDK1 activities. In the headpiece of the 4-(phenylaminomethylene)isoquinoline-1,3(2H,4H)-dione, a basic amine substituent is required on the aniline ring for the CDK4 inhibitory activity. The inhibitory activity is further enhanced when an aryl or heteroaryl substituent is introduced at the C-6 position of the isoquinoline-1,3(2H,4H)-dione core. We present here SAR data and a CDK4 mimic model that explains the binding, potency, and selectivity of our CDK4 selective inhibitors.
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ABSTRACT: In the present study, both classification and correlation approaches have been successfully employed for development of models for the prediction of CDK4 inhibitory activity using a dataset comprising of 52 analogues of 4-aminomethylene isoquinoline-1,3-(2H,4H)-dione. Decision tree, random forest, moving average analysis (MAA), multiple linear regression (MLR), partial least square regression (PLSR) and principal component regression (PCR) were used to develop models for prediction of CDK4 inhibitory activity. The statistical significance of models was assessed through specificity, sensitivity, overall accuracy, Mathew’s correlation coefficient (MCC), cross validated correlation coefficient, F test, r 2 for external test set (pred_r2), coefficient of correlation of predicted dataset (pred_ r2Se) and intercorrelation analysis. High accuracy of prediction offers proposed models a vast potential for providing lead structures for the development of potent therapeutic agents for CDK4 inhibition. Graphical Abstract Diverse classification and correlation techniques were successfully employed for the development of the models for the prediction of CDK4 inhibitory activity of substituted 4-aminomethylene isoquinoline-1, 3-diones.Journal of Chemical Sciences 05/2013; 125(3). DOI:10.1007/s12039-013-0410-1 · 1.19 Impact Factor
- Heterocycles 01/2009; 79(1). DOI:10.3987/COM-08-S(D)36 · 1.08 Impact Factor
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ABSTRACT: The series of 4-(benzylaminomethylene)isoquinoline-1,3-(2H,4H)-dione and 4-[(pyridylmethyl)aminomethylene]isoquinoline-1,3-(2H,4H)-dione derivatives reported here represents a novel class of potential antitumor agents, which potently and selectively inhibit CDK4 over CDK2 and CDK1. In the benzylamino headpiece, a 3-OH substituent is required on the phenyl ring for CDK4 inhibitory activity, which is further enhanced when an iodo, aryl, heteroaryl, t-butyl, or cyclopentyl substituent is introduced at the C-6 position of the isoquinoline-1,3-dione core. To circumvent the metabolic liability associated with the phenolic OH group on the 4-substituted 3-OH phenyl headpiece, we take two approaches: first, introduce a nitrogen o- or p- to the 3-OH group in the phenyl ring; second, replace the phenyl headpiece with N-substituted 2-pyridones. We present here the synthesis, SAR data, metabolic stability data, and a CDK4 mimic model that explains the binding, potency, and selectivity of our CDK4 selective inhibitors.Journal of Medicinal Chemistry 04/2009; 52(8):2289-310. DOI:10.1021/jm801026e · 5.45 Impact Factor
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