TY - JOUR
T1 - Enhanced Brain Delivery of 2-(Phosphonomethyl)pentanedioic Acid Following Intranasal Administration of Its γ-Substituted Ester Prodrugs
AU - Nedelcovych, Michael
AU - Dash, Ranjeet P.
AU - Tenora, Lukáš
AU - Zimmermann, Sarah C.
AU - Gadiano, Alexandra J.
AU - Garrett, Caroline
AU - Alt, Jesse
AU - Hollinger, Kristen R.
AU - Pommier, Elie
AU - Jančařík, Andrej
AU - Rojas, Camilo
AU - Thomas, Ajit G.
AU - Wu, Ying
AU - Wozniak, Krystyna
AU - Majer, Pavel
AU - Slusher, Barbara S.
AU - Rais, Rana
N1 - Funding Information:
This research was supported by an NIH R01CA161056 and P30MH075673-S1 and National Multiple Sclerosis Society grant (to B.S.S.) and the Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic v.v.i. (RVO 61388963).
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/10/2
Y1 - 2017/10/2
N2 - 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 γ-carboxylate. When compared to IN 2-PMPA in rats at 1 h post dose, γ-(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 (AUCIV: 76 ± 9 h·nmol/mL versus AUCIN: 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.
AB - 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 γ-carboxylate. When compared to IN 2-PMPA in rats at 1 h post dose, γ-(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 (AUCIV: 76 ± 9 h·nmol/mL versus AUCIN: 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.
KW - 2-PMPA
KW - glutamate carboxypeptidase II
KW - intranasal
KW - neurological disease
KW - pharmacokinetics
KW - prodrugs
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U2 - 10.1021/acs.molpharmaceut.7b00231
DO - 10.1021/acs.molpharmaceut.7b00231
M3 - Article
C2 - 28763226
AN - SCOPUS:85030650975
SN - 1543-8384
VL - 14
SP - 3248
EP - 3257
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 10
ER -