Enhanced Plasma Stability and Potency of Aryl/Acyloxy Prodrugs of a BTN3A1 Ligand

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-09-25 DOI:10.1021/acsmedchemlett.4c0037110.1021/acsmedchemlett.4c00371

Umed Singh, Girija Pawge, Sarita Rani, Chia-Hung Christine Hsiao, David F. Wiemer and Andrew J. Wiemer*,

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Abstract

While ester-based phosphonate prodrugs excel at delivering payloads into cells, their instability in plasma is a hurdle for their advancement. Here, we synthesized new aryl/acyloxy prodrugs of a phosphonate BTN3A1 ligand. We evaluated their phosphoantigen potency by flow cytometry and ELISA and their plasma and cellular metabolism by LC-MS. These compounds displayed low nanomolar to high picomolar potency. Addition of a p-isopropyl group to the phenyl substituent and use of cyclohexyl or p-methoxybenzyl groups as the acyloxy substituent significantly increased human, but not mouse or rat, plasma stability without negatively impacting potency. Combinations of these prodrug moieties further improved stability, with the best combination achieving a half-life of over 12 h in human plasma, a marked improvement on prior compounds. In contrast, oxane analogs improved water solubility and cellular payload delivery but remained unstable in human plasma. The studies suggest that certain ester-based phosphonate prodrugs quickly deliver active payloads inside cells and show substantial stability in human plasma.

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增强 BTN3A1 配体芳基/酰氧基原药的血浆稳定性和药效

虽然酯类膦酸盐原药在将有效载荷送入细胞方面表现出色，但它们在血浆中的不稳定性却阻碍了它们的发展。在这里，我们合成了膦酸盐 BTN3A1 配体的新芳基/酰氧基原药。我们通过流式细胞仪和酶联免疫吸附试验评估了它们的磷酸抗原效力，并通过 LC-MS 评估了它们的血浆和细胞代谢情况。这些化合物的效力从纳摩尔到皮摩尔不等。在苯基取代基上添加对异丙基，并使用环己基或对甲氧基苄基作为酰氧基取代基，可显著提高人血浆的稳定性，但不会影响小鼠或大鼠的药效。这些原药分子的组合进一步提高了稳定性，最佳组合在人血浆中的半衰期超过 12 小时，明显优于以前的化合物。相比之下，氧烷类似物提高了水溶性和细胞有效载荷的输送，但在人血浆中仍然不稳定。这些研究表明，某些酯类膦酸盐原药能在细胞内快速递送活性有效载荷，并在人血浆中表现出极高的稳定性。

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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.

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