title: Paclitaxel C-10 carbamates: potential candidates for the treatment of neurodegenerative tauopathies.
abstract: A series of paclitaxel C-10 carbamates was synthesized and evaluated in a bi-directional permeability assay in comparison with paclitaxel and the blood-brain barrier-permeable C-10 ester derivative, TX-67. A number of the carbamates were found not to be substrates for Pgp. Moreover, when tested for Pgp-inhibitory potential, representative compounds proved to be devoid of Pgp interactions. Side-by-side comparison between TX-67 and the corresponding C-10 carbamate, CNDR-3, revealed a significantly longer half-life for CNDR-3 in both mouse and human plasma, suggesting that this class of derivatives is appropriate for further in vivo evaluation.
authors.affiliation: Department of Chemistry, University of Pennsylvania, 231 South 34th St., Philadelphia, PA 19104-6323, USA. bcarlo@sas.upenn.edu <bcarlo@sas.upenn.edu>
authors.forename: Carlo
authors.initials: C
authors.lastname: Ballatore
authors.forename: Edward
authors.initials: E
authors.lastname: Hyde
authors.forename: Robert F
authors.initials: RF
authors.lastname: Deiches
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Donna
authors.initials: D
authors.lastname: Huryn
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D051379:Mice; D008956:Models, Chemical; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000494:pharmacology*; D010539:Permeability; D024801:Tauopathies / Q000188:drug therapy*; D013997:Time Factors
chemical_list: C497149:10-O-deacetylpaclitaxel 10-monosuccinyl ester; D002219:Carbamates; D017239:Paclitaxel