Discovery of tert-Butyl Ester Based 6-Diazo-5-oxo-l-norleucine Prodrugs for Enhanced Metabolic Stability and Tumor Delivery.
Discovery of tert-Butyl Ester Based 6-Diazo-5-oxo-l-norleucine Prodrugs for Enhanced Metabolic Stability and Tumor Delivery.
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DOI：
10.1021/acs.jmedchem.3c01681
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发表时间：
2023-11-23
影响因子：
7.3
通讯作者：
Rais, Rana
中科院分区：
文献类型：
--
作者：
Novotna, Katerina;Tenora, Lukas;Prchalova, Eva;Paule, James;Alt, Jesse;Veeravalli, Vijay;Lam, Jenny;Wu, Ying;Snajdr, Ivan;Gori, Sadakatali;Mettu, Vijaya Saradhi;Tsukamoto, Takashi;Majer, Pavel;Slusher, Barbara S.;Rais, Rana
谷氨酰胺拮抗剂6-重氮-5-氧代-l-正亮氨酸（DON）表现出显着的抗癌功效；然而，其治疗潜力因其对胃肠道（GI）组织的毒性而受到阻碍。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 的水溶性有限，并且其异丙酯基团的不稳定性导致形成无活性的 M1 代谢物，从而减少总体的全身前药暴露。在此，我们的目标是合成具有各种酯和酰胺基团的 DON 前药，以提高溶解度、胃肠道稳定性和 DON 肿瘤递送能力。合成了二十一种前药，并进行了稳定性和药代动力学研究。其中，P11，叔丁基-(S)-6-重氮-2-((S)-2-(2-(二甲基氨基)乙酰胺基)-3-苯基丙酰胺基)-5-氧代己酸酯，在血浆和肠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 理想的肿瘤靶向特性。总之，我们报告了具有改善的理化和药代动力学特性的新一代谷氨酰胺拮抗剂前药。
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.
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