Enhanced Oral Bioavailability of 2-(Phosphonomethyl)-pentanedioic Acid (2-PMPA) from its (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl (ODOL)-Based Prodrugs

Abstract

2-(Phosphonomethyl)-pentanedioic acid (2-PMPA) is a potent (IC50 = 300 pM) and selective inhibitor of glutamate carboxypeptidase II (GCPII) with efficacy in multiple neurological and psychiatric disease preclinical models and more recently in models of inflammatory bowel disease (IBD) and cancer. 2-PMPA (1), however, has not been clinically developed due to its poor oral bioavailability (<1%) imparted by its four acidic functionalities (c Log P = −1.14). In an attempt to improve the oral bioavailability of 2-PMPA, we explored a prodrug approach using (5-methyl-2-oxo-1,3-dioxol-4-yl)­methyl (ODOL), an FDA-approved promoiety, and systematically masked two (2), three (3), or all four (4) of its acidic groups. The prodrugs were evaluated for in vitro stability and in vivo pharmacokinetics in mice and dog. Prodrugs 2, 3, and 4 were found to be moderately stable at pH 7.4 in phosphate-buffered saline (57, 63, and 54% remaining at 1 h, respectively), but rapidly hydrolyzed in plasma and liver microsomes, across species. In vivo, in a single time-point screening study in mice, 10 mg/kg 2-PMPA equivalent doses of 2, 3, and 4 delivered significantly higher 2-PMPA plasma concentrations (3.65 ± 0.37, 3.56 ± 0.46, and 17.3 ± 5.03 nmol/mL, respectively) versus 2-PMPA (0.25 ± 0.02 nmol/mL). Given that prodrug 4 delivered the highest 2-PMPA levels, we next evaluated it in an extended time-course pharmacokinetic study in mice. 4 demonstrated an 80-fold enhancement in exposure versus oral 2-PMPA (AUC0–t : 52.1 ± 5.9 versus 0.65 ± 0.13 h*nmol/mL) with a calculated absolute oral bioavailability of 50%. In mouse brain, 4 showed similar exposures to that achieved with the IV route (1.2 ± 0.2 versus 1.6 ± 0.2 h*nmol/g). Further, in dogs, relative to orally administered 2-PMPA, 4 delivered a 44-fold enhanced 2-PMPA plasma exposure (AUC0–t for 4: 62.6 h*nmol/mL versus AUC0–t for 2-PMPA: 1.44 h*nmol/mL). These results suggest that ODOL promoieties can serve as a promising strategy for enhancing the oral bioavailability of multiply charged compounds, such as 2-PMPA, and enable its clinical translation.

N-Acetyl-Aspartyl-Glutamate in Brain Health and Disease

“…Barbara Slusher and colleagues recently reported to have synthesized prodrugs of nonthiol-based GCPII inhibitors with enhanced abilities to pass the blood-brain barrier [43,138]. They also explored intranasal administration [139] of GCPII inhibitors.…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

“…This prodrug also delivered a 44-fold enhanced 2-PMPA plasma exposure in further studies in dogs. Results demonstrate the applicability of the FDA approved ODOL promoiety in multiple charged drugs [5].…”

Phosphonates and Phosphonate Prodrugs in Medicinal Chemistry: Past Successes and Future Prospects

“…Despite its proven utility in multiple preclinical models, clinical use of 2-PMPA remains problematic due to its poor pharmacokinetic profile including low cellular uptake, low oral bioavailability, and minimal brain penetration caused by its strongly polar character. Given this, the IOCB and Johns Hopkins Drug Discovery collaborative team decided to focus on synthesizing 2-PMPA prodrugs ( Majer et al, 2016 ; Dash et al, 2019 ).…”

“…ODOL promoieties have been applied to enhance oral absorption of several FDA-approved drugs including olmesartan and azilsartan medoxomil ( Brousil and Burke, 2003 ; Babu et al, 2009 ; Garaga et al, 2015 ). 2-PMPA derivatives masked with two, three, or four ODOL groups were synthesised and evaluated for in vitro stability and in vivo pharmacokinetics in mice and dogs ( Dash et al, 2019 ). All prodrugs were found to be moderately stable at physiological pH, but rapidly hydrolysed in plasma and liver microsomes by the action of ubiquitous esterase enzymes.…”