OC144-093, a novel P glycoprotein inhibitor for the enhancement of anti-epileptic therapy.
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 FC50 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 microM 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.
Newman
Michael J
MJ
Ontogen Corporation, Carlsbad, CA 92009, USA.
Dixon
Ross
R
Toyonaga
Barry
B
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D017321:Clinical Trials, Phase I as Topic; D020650:Combinatorial Chemistry Techniques; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C410029:OC 144-093