NOVEL AZABICYCLOOCTANE INHIBITORS OF P-GLYCOPROTEIN

Cancer chemotherapy often provides temporary clinical improvement. However, tumor cells that survive the initial treatment often develop into cancers with multiple drug resistance (MDR). This is most often mediated by increased levels of the transport protein P-glycoprotein (PgP). A related family of transporters called MRPs are expressed by most normal tissues, and have complicated the development of therapies against MDR. Inhibitors of Pgp that do not concurrently inhibit MRPs are likely to be more effective clinical agents that previously tested non- selective MDR modulators. The overall goal of this project is to identify and characterize new compounds which are able to selectively overcome MDR. We have identified a new class of selective inhibitors of Pgp. Compound PGP-3005 is a substituted azabicyclo[2.2.2]octane that demonstrates excellent antagonism of Pgp in vitro, without affecting MRP1 activity. Further development of this class of MDR modulator supported by this SBIR Phase I grant will include: the design, synthesis and evaluation of additional azabicyclooctanes; and in vivo testing of either PGP-3005 or a superior analog for acute and delayed toxicity, pharmacokinetics and biodistribution and anti-MDR activity. These studies should allow a critical evaluation of the potential utility of this novel compound as a clinical agent. PROPOSED COMMERCIAL APPLICATIONS: P-glycoprotein mediated drug resistance is a very frequent limitation to successful chemotherapy of cancer. Compounds that effectively block this mechanism of resistance without altering the activities of related transport proteins could provide important therapeutic agents for a very large number of cancer patients. These compounds also have potential utility for improving drug delivery to the brain and enhancing the oral absorption of drugs.