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Cassette dosing pharmacokinetics of a library of 2,6,9-trisubstituted purine cyclin-dependent kinase 2 inhibitors prepared by parallel synthesis
Determination of pharmacokinetic properties in the intact animal remains a major bottleneck in drug discovery. Cassette dosing involves administration of a cocktail of drugs to individual animals. Here we describe the cassette dosing properties of a 107-membered library of 2,6,9-trisubstituted purin...
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Published in: | Molecular cancer therapeutics 2004-03, Vol.3 (3), p.353-362 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Determination of pharmacokinetic properties in the intact animal remains a major bottleneck in drug discovery. Cassette dosing
involves administration of a cocktail of drugs to individual animals. Here we describe the cassette dosing properties of a
107-membered library of 2,6,9-trisubstituted purine cyclin-dependent kinase 2 (CDK2) inhibitors. A three-step parallel synthesis
approach produced compounds with purity ranging from 63% to 100%. Cassette dosing was validated by comparing the pharmacokinetic
parameters obtained following i.v. administration of a mixture of olomoucine, R-roscovitine (CYC202), and bohemine, each at
16.6 mg/kg, with results for administration of single agents at 50 mg/kg. No significant difference was observed between the
pharmacokinetic parameters of agents when dosed in combination compared with those of individual compounds. CYC202 showed
the highest area under the curve (AUC) and the longest elimination half-life ( t 1/2 ). Further cassettes evaluated the library of trisubstituted purines with CYC202 and purvalanol A included as pharmacokinetic
standards in a validated limited sampling strategy. The ratios of pharmacokinetic parameters to that of CYC202 [AUC, maximum
concentration ( C max ), and t 1/2 ] remained similar when compounds were tested in two different cassettes or as individual compounds. Following dosing of the
same cassette on three different days, there was less than 20% variation in pharmacokinetic parameters between days. The structure-pharmacokinetics
relationship showed that the favored purine substituents are benzylamine and veratrylamine at position 6, amino-2 propanol
at position 2, and methylpropyl or hydroxyethyl at position 9. Without cassette dosing, this study would have used 3 times
as many animals and would have taken 4 times longer, illustrating the power of this method in lead optimization. |
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ISSN: | 1535-7163 1538-8514 |
DOI: | 10.1158/1535-7163.353.3.3 |