Lee Chae Bin, Šnajdr Ivan, Tenora Lukáš, Alt Jesse, Gori Sadakatali, Krečmerová Marcela, Maragakis R Michael, Paule James, Tiwari Sandhya, Iyer Jitesh, Talwar Rashmi, Garza Luis, Majer Pavel, Slusher Barbara S, Rais Rana
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Prague 160 00, Czech Republic.
In Vitro Biology, Sun Pharma Advanced Research Company Ltd., Plot #5 & 6/1, Savli GIDC, Manjusar, Vadodara 391775, Gujarat, India.
J Med Chem. 2025 Feb 13;68(3):3433-3444. doi: 10.1021/acs.jmedchem.4c02646. Epub 2025 Jan 23.
Itaconate, an endogenous immunomodulator from the tricarboxylic acid (TCA) cycle, shows therapeutic effects in various disease models, but is highly polar with poor cellular permeability. We previously reported a novel, topical itaconate derivative, SCD-153, for the treatment of alopecia areata. Here, we present the discovery of orally available itaconate derivatives for systemic and skin disorders. Four sets of prodrugs were synthesized using pivaloyloxymethyl (POM), isopropyloxycarbonyloxymethyl (POC), (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (ODOL), and 3-(hexadecyloxy)propyl (HDP) pro-moieties pairing with itaconic acid (IA), 1-methyl itaconate (1-MI), and 4-methyl itaconate (4-MI). Among these, POC-based prodrugs (, , ) showed favorable stability, permeability, and pharmacokinetics. Notably, and significantly inhibited Poly(I:C)/IFNγ-induced inflammatory cytokines in human epidermal keratinocytes. Oral studies demonstrated favorable pharmacokinetics releasing micromolar concentrations of IA or 4-MI from and , respectively. These findings highlight the potential of prodrug strategies to enhance itaconate's cellular permeability and oral bioavailability, paving the way for clinical translation.
衣康酸是一种来自三羧酸（TCA）循环的内源性免疫调节剂，在各种疾病模型中显示出治疗效果，但极性很高，细胞通透性差。我们之前报道了一种新型的局部用衣康酸衍生物SCD-153，用于治疗斑秃。在此，我们介绍了可口服的衣康酸衍生物在全身和皮肤疾病治疗方面的发现。使用新戊酰氧基甲基（POM）、异丙氧基羰氧基甲基（POC）、（5-甲基-2-氧代-1,3-二氧戊环-4-基）甲基（ODOL）和3-（十六烷氧基）丙基（HDP）前体基团与衣康酸（IA）、1-甲基衣康酸（1-MI）和4-甲基衣康酸（4-MI）合成了四组前药。其中，基于POC的前药（，，）表现出良好的稳定性、通透性和药代动力学。值得注意的是，和显著抑制了聚肌苷酸:聚胞苷酸（Poly(I:C)）/干扰素γ（IFNγ）诱导的人表皮角质形成细胞中的炎性细胞因子。口服研究表明，和分别释放微摩尔浓度的IA或4-MI，具有良好的药代动力学。这些发现突出了前药策略在提高衣康酸细胞通透性和口服生物利用度方面的潜力，为临床转化铺平了道路。
