Počet záznamů: 1
Enhanced Brain Delivery of 2-(Phosphonomethyl)pentanedioic Acid Following Intranasal Administration of Its gamma-Substituted Ester Prodrugs
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SYSNO ASEP 0480357 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Enhanced Brain Delivery of 2-(Phosphonomethyl)pentanedioic Acid Following Intranasal Administration of Its gamma-Substituted Ester Prodrugs Tvůrce(i) Nedelcovych, M. (US)
Dash, R. P. (US)
Tenora, Lukáš (UOCHB-X) ORCID
Zimmermann, S. C. (US)
Gadiano, A. J. (US)
Garrett, C. (US)
Alt, J. (US)
Hollinger, K. R. (US)
Pommier, E. (US)
Jančařík, Andrej (UOCHB-X) ORCID, RID
Rojas, C. (US)
Thomas, A. G. (US)
Wu, Y. (US)
Wozniak, K. (US)
Majer, Pavel (UOCHB-X)
Slusher, B. S. (US)
Rais, R. (US)Zdroj.dok. Molecular Pharmaceutics. - : American Chemical Society - ISSN 1543-8384
Roč. 14, č. 10 (2017), s. 3248-3257Poč.str. 10 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova 2-PMPA ; glutamate carboxypeptidase II ; neurological disease ; intranasal ; pharmacokinetics ; prodrugs Vědní obor RIV CC - Organická chemie Obor OECD Organic chemistry Institucionální podpora UOCHB-X - RVO:61388963 UT WOS 000412379100002 EID SCOPUS 85030650975 DOI 10.1021/acs.molpharmaceut.7b00231 Anotace 2-(Phosphonomethyl)pentanedioic acid (2-PMPA) is a potent and selective inhibitor of glutamate carboxypeptidase-II (GCPII) with efficacy in multiple neurological and psychiatric disease models, but its clinical utility is hampered by low brain penetration due to the inclusion of multiple acidic functionalities. We recently reported an improvement in the brain-to-plasma ratio of 2-PMPA after intranasal (IN) dosing in both rodents and primates. Herein, we describe the synthesis of several 2-PMPA prodrugs with further improved brain delivery of 2-PMPA after IN administration by masking of the gamma-carboxylate. When compared to IN 2-PMPA in rats at 1 h post dose, gamma-(4-acetoxybenzyl)-2-PMPA (compound 1) resulted in significantly higher 2-PMPA delivery to both plasma (4.1-fold) and brain (11-fold). Subsequent time-dependent evaluation of 1 also showed high brain as well as plasma 2-PMPA exposures with brain-to-plasma ratios of 2.2, 0.48, and 0.26 for olfactory bulb, cortex, and cerebellum, respectively, as well as an improved sciatic nerve to plasma ratio of 0.84. In contrast, IV administration of compound 1 resulted in similar plasma exposure of 2-PMPA versus the IN route (AUC(IN): 76 +/- 9 h.nmol/mL versus AUC(IN): 99 +/- 24 h.nmol/mL), but significantly lower nerve and brain tissue exposures with tissue-to-plasma ratios of 0.21, 0.03, 0.04, and 0.04 in nerve, olfactory bulb, cortex, and cerebellum, respectively. In primates, IN administration of 1 more than doubled 2-PMPA concentrations in the cerebrospinal fluid relative to previously reported levels following IN 2-PMPA. The results of these experiments provide a promising strategy for testing GCPII inhibition in neurological and psychiatric disorders. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Rok sběru 2018
Počet záznamů: 1