Prodrugs 2-(Phosphonomethyl)pentanedioic Acid (2-PMPA) as Orally Available Glutamate Carboxypeptidase II Inhibitors

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-08-19 DOI:10.1021/acsmedchemlett.5c00384

Niyada Hin, Chae Bin Lee, Sadakatali Gori, Barbara S. Slusher, Rana Rais and Takashi Tsukamoto*,

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引用次数: 0

Abstract

2-(Phosphonomethyl)pentanedioic acid (2-PMPA) is one of the most potent inhibitors of glutamate carboxypeptidase II (GCPII), a zinc metallopeptidase that cleaves glutamate from N-acetylaspartylglutamic acid and folylpoly-γ-glutamate. Due to the presence of multiple acidic groups, 2-PMPA exhibits poor oral bioavailability, limiting its therapeutic utility despite its potent GCPII inhibitory activity. One approach to address this challenge is to develop prodrugs of 2-PMPA with enhanced lipophilicity and improved oral absorption as demonstrated by tris-POC-2-PMPA and tetra-ODOL-2-PMPA. To expand the diversity of our prodrug strategy for 2-PMPA, we explored two promoieties for the phosphonate group of 2-PMPA, ProTide and cycloSal groups, while converting the two carboxylic acids to ester promoieties. The resulting prodrugs were assessed for their ability to deliver 2-PMPA in plasma in mice following oral administration. Among them, several cycloSal-based prodrugs delivered micromolar levels of 2-PMPA in plasma following oral administration, representing another effective prodrug strategy to orally deliver 2-PMPA.

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前药2-（磷甲乙基）戊二酸（2- pmpa）作为口服谷氨酸羧肽酶II抑制剂。

2-（磷甲乙基）戊二酸（2- pmpa）是谷氨酸羧肽酶II （GCPII）最有效的抑制剂之一，GCPII是一种锌金属肽酶，可从n -乙酰天冬氨酸和酰基聚γ-谷氨酸中切割谷氨酸。由于存在多个酸性基团，2-PMPA表现出较差的口服生物利用度，限制了其治疗效用，尽管它具有强大的GCPII抑制活性。解决这一挑战的一种方法是开发具有增强亲脂性和改善口服吸收的2-PMPA前药，如tris-POC-2-PMPA和tetrao - odol2 - pmpa。为了扩大我们的2-PMPA前药策略的多样性，我们探索了2-PMPA的磷酸基，ProTide和cycloSal基团的两个促进基团，同时将两个羧酸转化为酯促进基团。在口服给药后，评估了所得前药在小鼠血浆中传递2-PMPA的能力。其中，几种环盐类前药在口服后可在血浆中递送微摩尔水平的2-PMPA，这是口服2-PMPA的另一种有效前药策略。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.