Investigational New Drugs

, Volume 30, Issue 6, pp 2263–2273

Screening candidate anticancer drugs for brain tumor chemotherapy: Pharmacokinetic-driven approach for a series of (E)-N-(substituted aryl)-3-(substituted phenyl)propenamide analogues

Authors

  • Hua Lv
    • Department of Pharmacology and Systems TherapeuticsMount Sinai School of Medicine
    • Department of Pharmacology and System TherapeuticsMount Sinai School of Medicine
  • Fan Wang
    • Department of Pharmacology and Systems TherapeuticsMount Sinai School of Medicine
    • Department of Pharmacology and System TherapeuticsMount Sinai School of Medicine
  • M. V. Ramana Reddy
    • Department of Oncological SciencesMount Sinai School of Medicine
  • Qingyu Zhou
    • Department of Pharmacology and Systems TherapeuticsMount Sinai School of Medicine
  • Xiaoping Zhang
    • Department of Pharmacology and Systems TherapeuticsMount Sinai School of Medicine
  • E. Premkumar Reddy
    • Department of Oncological SciencesMount Sinai School of Medicine
    • Department of Pharmacology and Systems TherapeuticsMount Sinai School of Medicine
    • Department of Pharmacology and System TherapeuticsMount Sinai School of Medicine
PRECLINICAL STUDIES

DOI: 10.1007/s10637-012-9806-x

Cite this article as:
Lv, H., Wang, F., Reddy, M.V.R. et al. Invest New Drugs (2012) 30: 2263. doi:10.1007/s10637-012-9806-x

Summary

A pharmacokinetic [PK]-driven screening process was implemented to select new agents for brain tumor chemotherapy from a series of low molecular weight anticancer agents [ON27x] that consisted of 141 compounds. The screening procedures involved a combination of in silico, in vitro and in vivo mouse studies that were cast into a pipeline of tier 1 and tier 2 failures that resulted in a final investigation of 2 analogues in brain tumor-bearing mice. Tier 1 failures included agents with a molecular weight of > 450 Da, a predicted log P (log P) of either <2 or > 3.5, and a cytotoxicity IC50 value of > 2 uM. Next, 18 compounds underwent cassette dosing studies in normal mice that identified compounds with high systemic clearance, and low blood–brain barrier [BBB] penetration. These indices along with a derived parameter, referred to as the brain exposure index, comprised tier 2 failures that led to the administration of 2 compounds [ON27570, ON27740] as single agents [discrete dosing] to mice bearing intracerebral tumors. Comparison of ON27570’s resultant PK parameters to those obtained in the cassette dosing format suggested a drug-drug interaction most likely at the level of BBB transport, and prompted the use of the in vitro MDCK-MDR1 transport model to help assess the nature of the discrepancy. Overall, the approach was able to identify candidate compounds with suitable PK characteristics yet further revisions to the method, such as the use of in vitro metabolism and transport assays, may improve the PK-directed approach to identify efficacious agents for brain tumor chemotherapy.

Keywords

PharmacokineticsDrug developmentBrain tumorCNSPreclinical

Supplementary material

10637_2012_9806_MOESM1_ESM.doc (151 kb)
ESM 1(DOC 151 kb)

Copyright information

© Springer Science+Business Media, LLC 2012