Discovery of tert-Butyl Ester Based 6-Diazo-5-oxo-l-norleucine Prodrugs for Enhanced Metabolic Stability and Tumor Delivery,Journal of Medicinal Chemistry

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Discovery of tert-Butyl Ester Based 6-Diazo-5-oxo-l-norleucine Prodrugs for Enhanced Metabolic Stability and Tumor Delivery
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-11-10 , DOI: 10.1021/acs.jmedchem.3c01681
Kateřina Novotná _{1,

2} , Lukáš Tenora ₁ , Eva Prchalová ₁ , James Paule , Jesse Alt , Vijay Veeravalli , Jenny Lam , Ying Wu , Ivan Šnajdr ₁ , Sadakatali Gori , Vijaya Saradhi Mettu , Takashi Tsukamoto , Pavel Majer ₁ , Barbara S Slusher , Rana Rais

Affiliation

The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) exhibits remarkable anticancer efficacy; however, its therapeutic potential is hindered by its toxicity to gastrointestinal (GI) tissues. We recently reported the discovery of DRP-104, a tumor-targeted DON prodrug with excellent efficacy and tolerability, which is currently in clinical trials. However, DRP-104 exhibits limited aqueous solubility, and the instability of its isopropyl ester promoiety leads to the formation of an inactive M1-metabolite, reducing overall systemic prodrug exposure. Herein, we aimed to synthesize DON prodrugs with various ester and amide promoieties with improved solubility, GI stability, and DON tumor delivery. Twenty-one prodrugs were synthesized and characterized in stability and pharmacokinetics studies. Of these, P11, tert-butyl-(S)-6-diazo-2-((S)-2-(2-(dimethylamino)acetamido)-3-phenylpropanamido)-5-oxo-hexanoate, showed excellent metabolic stability in plasma and intestinal homogenate, high aqueous solubility, and high tumor DON exposures and preserved the ideal tumor-targeting profile of DRP-104. In conclusion, we report a new generation of glutamine antagonist prodrugs with improved physicochemical and pharmacokinetic attributes.

中文翻译：

发现基于叔丁酯的 6-重氮-5-氧代-l-去甲亮氨酸前药，用于增强代谢稳定性和肿瘤递送

谷氨酰胺拮抗剂 6-重氮-5-氧代-l-去甲亮氨酸（DON）表现出显着的抗癌功效;然而，其治疗潜力受到其对胃肠道（GI）组织的毒性的阻碍。我们最近报道了 DRP-104 的发现，这是一种具有优异疗效和耐受性的肿瘤靶向 DON 前药，目前正在进行临床试验。然而，DRP-104 表现出有限的水溶性，并且其异丙酯促进性的不稳定性导致形成无活性的 M1 代谢物，从而减少整体全身前药暴露。在此，我们旨在合成具有各种酯和酰胺促进性的 DON 前药，具有更好的溶解度、GI 稳定性和 DON 肿瘤递送。合成了 21 种前药，并在稳定性和药代动力学研究中进行了表征。其中，P11，叔丁基-（S）-6-重氮-2-（（S）-2-（2-（二甲氨基）乙酰氨基）-3-苯基丙酰胺）-5-氧代-己酸酯，在血浆和肠道匀浆中表现出优异的代谢稳定性、高水溶性和高肿瘤 DON 暴露，并保留了 DRP-104 的理想肿瘤靶向特征。总之，我们报道了具有改进的理化和药代动力学属性的新一代谷氨酰胺拮抗剂前药。

更新日期：2023-11-10

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