PURPOSE: Prostate-specific membrane antigen (PSMA) radioligand therapy is a promising treatment for metastatic castration-resistant prostate cancer (mCRPC). Several beta or alpha particle-emitting radionuclide-conjugated small molecules have shown efficacy in late-stage mCRPC and one, [[177Lu]Lu]Lu-PSMA-617, is FDA approved. In addition to tumor upregulation, PSMA is also expressed in kidneys and salivary glands where specific uptake can cause dose-limiting xerostomia and potential for nephrotoxicity. The PSMA inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) can prevent kidney uptake in mice, but also blocks tumor uptake, precluding its clinical utility. Preferential delivery of 2-PMPA to non-malignant tissues could improve the therapeutic window of PSMA radioligand therapy. METHODS: A tris(isopropoxycarbonyloxymethyl) (TrisPOC) prodrug of 2-PMPA, JHU-2545, was synthesized to enhance 2-PMPA delivery to non-malignant tissues. Mouse pharmacokinetic experiments were conducted to compare JHU-2545-mediated delivery of 2-PMPA to plasma, kidney, salivary glands, and C4-2 prostate tumor xenograft. Imaging studies were conducted in rats and mice to measure uptake of PSMA PET tracers in kidney, salivary glands, and prostate tumor xenografts with and without JHU-2545 pre-treatment. RESULTS: JHU-2545 resulted in approximately 3- and 53-fold greater exposure of 2-PMPA in rodent salivary glands (18.0 ± 0.97 h*nmol/g) and kidneys (359 ± 4.16 h*nmol/g) versus prostate tumor xenograft (6.79 ± 0.19 h*nmol/g). JHU-2545 also blocked rodent kidneys and salivary glands uptake of the PSMA PET tracers [68Ga]Ga-PSMA-11 and [18 F]F-DCFPyL by up to 85% with little effect on tumor. CONCLUSIONS: JHU-2545 pre-treatment may enable greater cumulative administered doses of PSMA radioligand therapy, possibly improving safety and efficacy.

• Klíčová slova
• Kidneys, PSMA, Prostate cancer, Radioligand therapy, Salivary glands,
• MeSH
• antigeny povrchové * metabolismus   MeSH
• glutamátkarboxypeptidasa II * metabolismus   MeSH
• krysa rodu Rattus MeSH
• ledviny * účinky léků   diagnostické zobrazování   metabolismus   účinky záření   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• radioprotektivní látky * farmakologie   farmakokinetika   MeSH
• slinné žlázy * účinky léků   diagnostické zobrazování   metabolismus   účinky záření   MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny povrchové * MeSH
• FOLH1 protein, human MeSH Prohlížeč
• glutamátkarboxypeptidasa II * MeSH
• radioprotektivní látky * MeSH

Itaconate, an endogenous immunomodulator from the tricarboxylic acid (TCA) cycle, shows therapeutic effects in various disease models, but is highly polar with poor cellular permeability. We previously reported a novel, topical itaconate derivative, SCD-153, for the treatment of alopecia areata. Here, we present the discovery of orally available itaconate derivatives for systemic and skin disorders. Four sets of prodrugs were synthesized using pivaloyloxymethyl (POM), isopropyloxycarbonyloxymethyl (POC), (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (ODOL), and 3-(hexadecyloxy)propyl (HDP) pro-moieties pairing with itaconic acid (IA), 1-methyl itaconate (1-MI), and 4-methyl itaconate (4-MI). Among these, POC-based prodrugs (P2, P9, P13) showed favorable stability, permeability, and pharmacokinetics. Notably, P2 and P13 significantly inhibited Poly(I:C)/IFNγ-induced inflammatory cytokines in human epidermal keratinocytes. Oral studies demonstrated favorable pharmacokinetics releasing micromolar concentrations of IA or 4-MI from P2 and P13, respectively. These findings highlight the potential of prodrug strategies to enhance itaconate's cellular permeability and oral bioavailability, paving the way for clinical translation.

• MeSH
• aplikace orální MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• myši MeSH
• objevování léků MeSH
• prekurzory léčiv * chemie   farmakologie   chemická syntéza   farmakokinetika   MeSH
• sukcináty * chemie   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• itaconic acid MeSH Prohlížeč
• prekurzory léčiv * MeSH
• sukcináty * MeSH

Compounds with a phosphonate group, i.e., -P(O)(OH)2 group attached directly to the molecule via a P-C bond serve as suitable non-hydrolyzable phosphate mimics in various biomedical applications. In principle, they often inhibit enzymes utilizing various phosphates as substrates. In this review we focus mainly on biologically active phosphonates that originated from our institute (Institute of Organic Chemistry and Biochemistry in Prague); i.e., acyclic nucleoside phosphonates (ANPs, e.g., adefovir, tenofovir, and cidofovir) and derivatives of non-nucleoside phosphonates such as 2-(phosphonomethyl) pentanedioic acid (2-PMPA). Principal strategies of their syntheses and modifications to prodrugs is reported. Besides clinically used ANP antivirals, a special attention is paid to new biologically active molecules with respect to emerging infections and arising resistance of many pathogens against standard treatments. These new structures include 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidines or so-called "open-ring" derivatives, acyclic nucleoside phosphonates with 5-azacytosine as a base moiety, side-chain fluorinated ANPs, aza/deazapurine ANPs. When transformed into an appropriate prodrug by derivatizing their charged functionalities, all these compounds show promising potential to become drug candidates for the treatment of viral infections. ANP prodrugs with suitable pharmacokinetics include amino acid phosphoramidates, pivaloyloxymethyl (POM) and isopropoxycarbonyloxymethyl (POC) esters, alkyl and alkoxyalkyl esters, salicylic esters, (methyl-2-oxo-1,3-dioxol-4-yl) methyl (ODOL) esters and peptidomimetic prodrugs. We also focus on the story of cytostatics related to 9-[2-(phosphonomethoxy)ethyl]guanine and its prodrugs which eventually led to development of the veterinary drug rabacfosadine. Various new ANP structures are also currently investigated as antiparasitics, especially antimalarial agents e.g., guanine and hypoxanthine derivatives with 2-(phosphonoethoxy)ethyl moiety, their thia-analogues and N-branched derivatives. In addition to ANPs and their analogs, we also describe prodrugs of 2-(phosphonomethyl)pentanedioic acid (2-PMPA), a potent inhibitor of the enzyme glutamate carboxypeptidase II (GCPII), also known as prostate-specific membrane antigen (PSMA). Glutamate carboxypeptidase II inhibitors, including 2-PMPA have been found efficacious in various preclinical models of neurological disorders which are caused by glutamatergic excitotoxicity. Unfortunately its highly polar character and hence low bioavailability severely limits its potential for clinical use. To overcome this problem, various prodrug strategies have been used to mask carboxylates and/or phosphonate functionalities with pivaloyloxymethyl, POC, ODOL and alkyl esters. Chemistry and biological characterization led to identification of prodrugs with 44-80 fold greater oral bioavailability (tetra-ODOL-2-PMPA).

• Klíčová slova
• 2-PMPA, FOLH1, GCPII, acyclic nucleoside phosphonates, antivirals, prodrugs, prostate-specific membrane antigen, protides,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

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.

• Klíčová slova
• 2-PMPA, glutamate carboxypeptidase II, oral bioavailability, pharmacokinetics, prodrugs,
• MeSH
• aplikace orální MeSH
• biologická dostupnost MeSH
• jaterní mikrozomy metabolismus   MeSH
• myši MeSH
• organofosforové sloučeniny aplikace a dávkování   chemie   metabolismus   farmakokinetika   MeSH
• prekurzory léčiv aplikace a dávkování   chemie   metabolismus   farmakokinetika   MeSH
• psi MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• 2-(phosphonomethyl)pentanedioic acid MeSH Prohlížeč
• organofosforové sloučeniny MeSH
• prekurzory léčiv MeSH

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.

• Klíčová slova
• 2-PMPA, glutamate carboxypeptidase II, intranasal, neurological disease, pharmacokinetics, prodrugs,
• MeSH
• aplikace intranazální MeSH
• estery analýza   chemie   farmakologie   MeSH
• glutamátkarboxypeptidasa II antagonisté a inhibitory   MeSH
• hematoencefalická bariéra účinky léků   MeSH
• intravenózní podání MeSH
• krysa rodu Rattus MeSH
• Macaca mulatta MeSH
• mozek účinky léků   MeSH
• mozkomíšní mok účinky léků   MeSH
• neuroprotektivní látky analýza   chemie   farmakologie   MeSH
• organofosforové sloučeniny analýza   chemie   farmakologie   MeSH
• potkani Wistar MeSH
• prekurzory léčiv analýza   chemie   farmakologie   MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• 2-(phosphonomethyl)pentanedioic acid MeSH Prohlížeč
• estery MeSH
• glutamátkarboxypeptidasa II MeSH
• neuroprotektivní látky MeSH
• organofosforové sloučeniny MeSH
• prekurzory léčiv MeSH

4-Carboxy-α-[3-(hydroxyamino)-3-oxopropyl]-benzenepropanoic acid 1 is a potent hydroxamate-based inhibitor of glutamate carboxypeptidase II. In an attempt to improve its poor oral pharmacokinetics, we synthesized a series of prodrugs by masking its hydrophilic hydroxamate group. Prodrugs were evaluated for oral availability in mice and showed varying degree of plasma exposure to 1. Of these, para-acetoxybenzyl-based, 4-(5-(((4-acetoxybenzyl)oxy)amino)-2-carboxy-5-oxopentyl)benzoic acid, 12, provided 5-fold higher plasma levels of 1 compared to oral administration of 1 itself. Subsequently, para-acetoxybenzyl-based prodrugs with additional ester promoiety(ies) on carboxylate(s) were examined for their ability to deliver 1 to plasma. Isopropyloxycarbonyloxymethyl (POC) ester 30 was the only prodrug that achieved substantial plasma levels of 1. In vitro metabolite identification studies confirmed stability of the ethyl ester of benzoate while the POC group was rapidly hydrolyzed. At oral daily dose-equivalent of 3 mg/kg, 12 exhibited analgesic efficacy comparable to dose of 10 mg/kg of 1 in the rat chronic constrictive injury model of neuropathic pain.

• MeSH
• analgetika chemie   farmakokinetika   farmakologie   terapeutické užití   MeSH
• aplikace orální MeSH
• esterifikace MeSH
• glutamátkarboxypeptidasa II antagonisté a inhibitory   metabolismus   MeSH
• inhibitory enzymů chemie   farmakokinetika   farmakologie   terapeutické užití   MeSH
• krysa rodu Rattus MeSH
• kyseliny hydroxamové chemie   farmakokinetika   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• myši MeSH
• neuralgie farmakoterapie   enzymologie   MeSH
• objevování léků MeSH
• potkani Sprague-Dawley MeSH
• prekurzory léčiv chemie   farmakokinetika   farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• analgetika MeSH
• glutamátkarboxypeptidasa II MeSH
• inhibitory enzymů MeSH
• kyseliny hydroxamové MeSH
• prekurzory léčiv MeSH

Glutamate carboxypeptidase II (GCPII), also known as prostate-specific membrane antigen (PSMA) or folate hydrolase, is a metallopeptidase expressed predominantly in the human brain and prostate. GCPII expression is considerably increased in prostate carcinoma, and the enzyme also participates in glutamate excitotoxicity in the brain. Therefore, GCPII represents an important diagnostic marker of prostate cancer progression and a putative target for the treatment of both prostate cancer and neuronal disorders associated with glutamate excitotoxicity. For the development of novel therapeutics, mouse models are widely used. However, although mouse GCPII activity has been characterized, a detailed comparison of the enzymatic activity and tissue distribution of the mouse and human GCPII orthologs remains lacking. In this study, we prepared extracellular mouse GCPII and compared it with human GCPII. We found that mouse GCPII possesses lower catalytic efficiency but similar substrate specificity compared with the human protein. Using a panel of GCPII inhibitors, we discovered that inhibition constants are generally similar for mouse and human GCPII. Furthermore, we observed highest expression of GCPII protein in the mouse kidney, brain, and salivary glands. Importantly, we did not detect GCPII in the mouse prostate. Our data suggest that the differences in enzymatic activity and inhibition profile are rather small; therefore, mouse GCPII can approximate human GCPII in drug development and testing. On the other hand, significant differences in GCPII tissue expression must be taken into account when developing novel GCPII-based anticancer and therapeutic methods, including targeted anticancer drug delivery systems, and when using mice as a model organism.

• Klíčová slova
• glutamate carboxypeptidase II, mouse animal model, neuronal disorders, prostate cancer, prostate‐specific membrane antigen,
• Publikační typ
• časopisecké články MeSH