Newman Michael J, Dixon Ross, Toyonaga Barry
Ontogen Corporation, Carlsbad, CA 92009, USA.
Novartis Found Symp. 2002;243:213-26; discussion 226-30, 231-5.
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.
P-糖蛋白（Pgp）抑制剂可能有助于增强抗癫痫药物（AED）的血脑屏障穿透能力。由于联合用药以及需要长期治疗，用于癫痫的Pgp抑制剂应具有高度特异性且无毒。特别是，使用对AED和癫痫患者使用的其他药物代谢所涉及的酶产生最小抑制作用的化合物可能至关重要。OC144-093是一种使用OntoBLOCK系统（一种固相组合化学技术）结合基于细胞的高通量筛选生成的新型取代二芳基咪唑。该化合物是癌症中Pgp介导的多药耐药性（MDR）的极强抑制剂，平均FC50为32 nM，但不抑制多药耐药相关蛋白（MRP1）。OC144-093是迄今为止描述的非特异性毒性最小的Pgp抑制剂，在15种细胞类型中的平均细胞生长抑制IC50>60 microM。它不会被参与AED代谢的细胞色素P450s CYP3A4、2C8或2C9酶代谢。OC144-093与紫杉醇不会产生药代动力学（PK）相互作用，并且在I期临床试验中表现出优异的PK和安全性。我们的结果表明，OC144-093可能是增强AED血脑屏障穿透能力的理想候选药物。
