Cannabidiol-Based Prodrugs: Synthesis and Bioevaluation

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-01-16 DOI:10.1021/acsmedchemlett.3c00461

Pankaj Singh Cham, Pankul Kotwal, Kuhu Sharma, Sumit Dhiman, Lakhvinder Singh, Varun Pratap Singh, Ajay Kumar, Utpal Nandi* and Parvinder Pal Singh*,

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Abstract

Cannabidiol (CBD 1) is a nonpsychotic cannabinoid-based drug approved by the U.S. FDA for treating refractory epilepsy, namely, Lennox–Gastaut and Dravet syndrome. However, its low aqueous solubility and oral bioavailability are compensated by administering high doses, and there is an increased demand for conjugates with improved properties. In this direction, the present work is focused on synthesizing CBD-based prodrugs to address the issue of poor solubility and oral bioavailability. Several CBD-based prodrugs were synthesized and studied in a battery of assays: viz, release kinetic (ex vivo), solubility (in vitro), chemical stability (in vitro), plasma stability (ex vivo), pharmacokinetics (in vivo), and efficacy studies (in vivo). Among the synthesized prodrugs, the morpholinyl CBD-based prodrugs 3a and 3aa showed good release behavior, stability, better solubility, and a plasma profile. Moreover, prodrug candidate 3aa showed better therapeutic efficacy. The present study identifies CBD-based prodrugs with improved physiochemical properties and oral exposure.

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基于大麻二酚的原药：合成与生物评估

大麻二酚（CBD 1）是美国 FDA 批准用于治疗难治性癫痫（即 Lennox-Gastaut 和 Dravet 综合征）的非精神类大麻素药物。然而，由于其水溶解度和口服生物利用度较低，需要通过大剂量给药来弥补，因此对具有更好特性的共轭物的需求日益增加。在此方向上，本研究的重点是合成基于 CBD 的原药，以解决溶解性和口服生物利用度差的问题。我们合成了几种基于 CBD 的原药，并对其进行了一系列研究：即释放动力学（体内外）、溶解度（体外）、化学稳定性（体外）、血浆稳定性（体内外）、药代动力学（体内）和药效研究（体内）。在合成的原药中，基于吗啉基 CBD 的原药 3a 和 3aa 表现出良好的释放行为、稳定性、较好的溶解性和血浆特征。此外，候选原药 3aa 表现出更好的疗效。本研究发现了具有更好的理化性质和口服暴露的 CBD 原药。

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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.