Enhanced Brain Delivery of 2-(Phosphonomethyl)pentanedioic Acid Following Intranasal Administration of Its gamma-Substituted Ester Prodrugs

0480357 - ÚOCHB 2018 RIV US eng J - Článek v odborném periodiku
Nedelcovych, M. - Dash, R. P. - Tenora, Lukáš - Zimmermann, S. C. - Gadiano, A. J. - Garrett, C. - Alt, J. - Hollinger, K. R. - Pommier, E. - Jančařík, Andrej - Rojas, C. - Thomas, A. G. - Wu, Y. - Wozniak, K. - Majer, Pavel - Slusher, B. S. - Rais, R.
Enhanced Brain Delivery of 2-(Phosphonomethyl)pentanedioic Acid Following Intranasal Administration of Its gamma-Substituted Ester Prodrugs.
Molecular Pharmaceutics. Roč. 14, č. 10 (2017), s. 3248-3257. ISSN 1543-8384. E-ISSN 1543-8392
Institucionální podpora: RVO:61388963
Klíčová slova: 2-PMPA * glutamate carboxypeptidase II * neurological disease * intranasal * pharmacokinetics * prodrugs
Obor OECD: Organic chemistry
Impakt faktor: 4.556, rok: 2017

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.
Trvalý link: http://hdl.handle.net/11104/0276143