Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China.
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China.
Eur J Med Chem. 2019 Nov 15;182:111589. doi: 10.1016/j.ejmech.2019.111589. Epub 2019 Aug 6.
A series of aryl-substituted indole and indoline derivatives were discovered as novel RORγt agonists by a scaffold-based hybridization of the reported RORγt agonists 1 and 2. SAR studies on the core structures, the RHS hydrophilic side chains and the LHS hydrophobic aryl groups of a hybrid compound 3 led to the identification of potent RORγt agonists with improved drug-like properties. Compound 14 represented a high potency lead with an EC of 20.8 ± 1.5 nM, the (S)-enantiomer (EC = 16.1 ± 4.5 nM) of which was 17 times more potent than the (R) counterpart (EC = 286 ± 30.4 nM) in RORγ dual FRET assay. The cell-based GAL4 reporter gene assay also suggested 14 as the most active compound which exhibited an EC of 247 ± 33.1 nM and a maximum activation percentage of 133%. Moreover, 14 showed high metabolic stability (t = 113 min) in mouse liver microsome and had improved aqueous solubility at pH 7.4 compared to the parent compounds. Furthermore, 14 was found to be orally bioavailable and demonstrated excellent in vivo pharmacokinetics in mice. Present studies indicate that 14 deserves further investigation in tumor animal models as a potential candidate of RORγt agonist for cancer immunotherapy.
一系列芳基取代的吲哚和吲哚啉衍生物被发现是新型 RORγt 激动剂，其通过报道的 RORγt 激动剂 1 和 2 的基于支架的杂交而产生。对杂种 3 的核心结构、RHS 亲水性侧链和 LHS 疏水性芳基的 SAR 研究导致了具有改善的类药性的有效 RORγt 激动剂的鉴定。化合物 14 代表了一种高活性的先导化合物，其 EC50 为 20.8±1.5nM，其（S）对映异构体（EC50=16.1±4.5nM）比（R）对映异构体（EC50=286±30.4nM）在 RORγ 双重 FRET 测定中具有 17 倍的活性。基于细胞的 GAL4 报告基因测定也表明 14 是最活跃的化合物，其 EC50 为 247±33.1nM，最大激活百分比为 133%。此外，与母体化合物相比，14 在小鼠肝微粒体中具有较高的代谢稳定性（t=113 分钟），并且在 pH 7.4 时具有改善的水溶解度。此外，发现 14 具有口服生物利用度，并在小鼠体内表现出良好的药代动力学。目前的研究表明，14 作为癌症免疫治疗的 RORγt 激动剂的潜在候选物，值得在肿瘤动物模型中进一步研究。
