Synthesis and characterization of reversible mometasone furoate dimers as P-glycoprotein inhibitors

Jenna Manby Ivers, Purdue University

Abstract

Several ABC (ATP-binding cassette) transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP, ABCG2), and the multidrug resistance proteins (MRPs) are expressed in tissues important for the uptake, metabolism, and elimination of xenobiotics. Their function protects tissues from the potentially toxic effects of foreign compounds. Transporter efflux also limits the access of numerous pharmaceuticals to their target tissues. P-gp is the best-characterized multidrug transporter and is expressed at high levels in the gut epithelium and blood brain barrier, where it limits the oral and brain bioavailability of its substrates. P-gp, therefore, is a hindrance to achieving therapeutic levels of pharmaceutical substrates in the blood and brain. The goal of our research is to enhance the oral and brain bioavailability of therapeutic P-gp substrates through reversible modulation of P-gp transport. This aim can be accomplished through the synthesis and characterization of dimeric prodrugs based on the therapeutic itself. Our inhibitors are synthesized by linking two therapeutic P-gp substrates via a degradable tether. The reversibility of our inhibitors gives them a bifunctional nature. In their dimeric form, the inhibitors are designed to prevent substrate efflux by occupying P-gp's multiple binding sites. Intracellular degradation of the dimer then allows for prodrug delivery of therapeutic monomer. This design strategy reduces the persistence of inhibition and eliminates the need for a co-administered inhibitor, decreasing the risk of toxic side affects. Our strategy has proved successful and is applicable to a diverse array of pharmaceutical agents, including brain-targeted therapies (i.e. antipsychotics, antiepileptic drugs, and antidepressants), antineoplastic agents, antiretrovirals, and antimalarials. We have investigated the ability of mometasone furoate homodimers to inhibit P-gp transport. Mometasone furoate was selected for dimerization because it inhibits P-gp transport and competes for substrate binding as potently as our most successful substrate dimers. We hypothesized that synthesis of mometasone furoate dimers may yield our most effective bivalent inhibitors to date. Although we have successfully synthesized mometasone furoate homodimers, our results suggest that they are unsuccessful as P-gp inhibitors. Study of this therapeutic inhibitor, however, should be continued.

Degree

M.S.

Advisors

Hrycyna, Purdue University.

Subject Area

Chemistry|Biochemistry

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