Discovery of Highly Potent Multidrug Resistance (MDR) Reversal Agents: Aminosulfonylaryl Isoxazole Derivatives

The overexpression of P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter, has been demonstrated not only to be primarily involved in the incapacitation of a variety of widely used anticancer agents, such as, paclitaxel (Taxol), doxorubicin, and vinorelbine, but also is observed much more frequently than other ABC transporters. However, despite the developments of a number of P-gp inhibitors to overcome MDR, no drug is currently clinically available. A number of drug candidates have been dropped because of critical limitations, such as, intrinsic toxicity and pharmacokinetic interactions. Furthermore, few accurate methods are available for identifying patients that might benefit from MDR inhibition. However, advanced functional imaging technology using