title: Dual Modulation of Human P-Glycoprotein and ABCG2 with Prodrug Dimers of the Atypical Antipsychotic Agent Paliperidone in a Model of the Blood-Brain Barrier.
abstract: Many atypical antipsychotic drugs currently prescribed for the treatment of schizophrenia have limited brain penetration due to the efflux activity of ATP-binding cassette (ABC) transporters at the blood-brain barrier (BBB), including P-glycoprotein (P-gp) and ABCG2. Herein, we describe the design and synthesis of the first class of homodimeric prodrug dual inhibitors of P-gp and ABCG2. These inhibitors are based on the structure of the atypical antipsychotic drug paliperidone (Pal), a transport substrate for both transporters. We synthesized and characterized a small library of homodimeric bivalent Pal inhibitors that contain a variety of tethers joining the two monomers via ester linkages. The majority of our compounds were low micromolar to sub-micromolar inhibitors of both P-gp and ABCG2 in cells overexpressing these transporters and in immortalized human hCMEC/D3 cells that are derived from the BBB. Our most potent dual inhibitor also contained an internal disulfide bond in the tether (Pal-8SS) that allowed for rapid reversion to monomer in the presence of reducing agents or plasma esterases. To increase stability against these esterases, we further engineered Pal-8SS to contain two hindering methyl groups alpha to the carbonyl of the ester moiety within the tether. The resulting dimer, Pal-8SSMe, was also a potent dual inhibitor that remained susceptible to reducing conditions but was more resistant to breakdown in human plasma. Importantly, Pal-8SSMe both accumulated and subsequently reverted to the therapeutic Pal monomer in the reducing environment of BBB cells. Thus, these molecules serve two purposes, acting as both inhibitors of P-gp and ABCG2 at the BBB and as prodrugs, effectively delivering therapies to the brain that would otherwise be precluded.
authors.affiliation: Department of Chemistry and Institute for Integrative Neuroscience, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Bohn
authors.affiliation: Department of Chemistry and Institute for Integrative Neuroscience, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Allison
authors.initials: A
authors.lastname: Lange
authors.affiliation: Department of Chemistry and Institute for Integrative Neuroscience, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Jean
authors.initials: J
authors.lastname: Chmielewski
authors.affiliation: Department of Chemistry and Institute for Integrative Neuroscience, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Christine A
authors.identifier: 0000-0001-9881-2063
authors.initials: CA
authors.lastname: Hrycyna
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D061986:MCF-7 Cells; D009363:Neoplasm Proteins / Q000378:metabolism*; D000068882:Paliperidone Palmitate / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*
chemical_list: C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D014150:Antipsychotic Agents; D009363:Neoplasm Proteins; D011355:Prodrugs; D000068882:Paliperidone Palmitate
keywords: ABC transporter; atypical antipsychotic; blood−brain barrier; drug transport