OC144-093, a Novel P glycoprotein Inhibitor for the Enhancement of Anti-Epileptic Therapy

  1. Gregory Bock and
  2. Jamie A. Goode
  1. Michael J. Newman,
  2. Ross Dixon and
  3. Barry Toyonaga

Published Online: 7 OCT 2008

DOI: 10.1002/0470846356.ch16

Mechanisms of Drug Resistance in Epilepsy: Novartis Foundation Symposium 243

Mechanisms of Drug Resistance in Epilepsy: Novartis Foundation Symposium 243

How to Cite

Newman, M. J., Dixon, R. and Toyonaga, B. (2002) OC144-093, a Novel P glycoprotein Inhibitor for the Enhancement of Anti-Epileptic Therapy, in Mechanisms of Drug Resistance in Epilepsy: Novartis Foundation Symposium 243 (eds G. Bock and J. A. Goode), John Wiley & Sons, Ltd, Chichester, UK. doi: 10.1002/0470846356.ch16

Author Information

  1. Ontogen Corporation, 6451 El Camino Real, Carlsbad, CA 92009, USA

Publication History

  1. Published Online: 7 OCT 2008
  2. Published Print: 25 MAR 2002

Book Series:

  1. Novartis Foundation Symposia

Book Series Editors:

  1. Novartis Foundation

ISBN Information

Print ISBN: 9780470841464

Online ISBN: 9780470846353

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Summary

Inhibitors of P glycoprotein (Pgp) may be useful for the enhancement of blood–brain barrier penetration of anti-epileptic drugs (AEDs). Due to polypharmacy and the need for chronic treatment, Pgp inhibitors used in epilepsy should be highly specific and non-toxic. In particular, it may be essential to use compounds that produce minimal inhibition of enzymes involved in metabolism of AEDs and other drugs used by epilepsy patients. OC144-093 is a novel substituted diarylimidazole generated using the OntoBLOCK® system, a solid-phase combinatorial chemistry technology, in combination with high-throughput cell-based screening. The compound is an extremely potent inhibitor of Pgp-mediated multidrug resistance (MDR) in cancer with an average EC50 of 32 nM, but does not inhibit multidrug resistance-associated protein (MRP1). OC144-093 is the least non-specifically toxic Pgp inhibitor described to date, with an average cytostatic IC50 of >60 µM in 15 cell types. It is not metabolized by cytochrome P450s CYP3A4, 2C8 or 2C9 enzymes involved in AED metabolism. OC144-093 does not produce a pharmacokinetic (PK) interaction with paclitaxel and has exhibited an excellent PK and safety profile in phase I clinical trials. Our results suggest that OC144-093 may represent an ideal candidate for use in enhancement of AED blood–brain barrier penetration.