State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
Eur J Med Chem. 2020 Mar 1;189:112059. doi: 10.1016/j.ejmech.2020.112059. Epub 2020 Jan 11.
Indoleamine 2,3-dioxygenase 1 (IDO1) is the enzyme catalyzing the oxidative metabolism of tryptophan, which accounts for cancer immunosuppression in tumor microenvironment. Several compounds targeting IDO1 have been reported and epacadostat shows strong inhibitory activity against IDO1, which is further studied in clinic trails. However, its pharmacokinetic profiles are not satisfactory. The half-life of epacadostat is 2.4 h in human and dosage is 50 mg BID in the phase III clinic trial. To overcome the shortcomings of epacadostat, structure-based drug design was performed to improve the pharmacokinetic profiles via changing the metabolic pathway of epacadostat and to enhance anti-tumor potency. A novel series of 1,2,5-oxadiazole-3-carboximidamide derivatives bearing cycle in the side chain were designed, synthesized, and biologically evaluated for their anti-tumor activity. Most of them exhibited potent activity against hIDO1 in enzymatic assays and in HEK293T cells over-expressing hIDO1. Among them, compound 23, 25 and 26 showed significant inhibitory activity against hIDO1 (IC = 108.7, 178.1 and 139.1 nM respectively) and in HEK293T cells expressing hIDO1 (cellular IC = 19.88, 68.59 and 57.76 nM respectively). Moreover, compound 25 displayed improved PK property with longer half-life (t = 3.81 h in CD-1 mice) and better oral bioavailability (F = 33.6%) compared with epacadostat. In addition, compound 25 showed similar potency to inhibit the growth of CT-26 syngeneic xenograft compared to epacadostat, making it justifiable for further investigation.
吲哚胺 2,3-双加氧酶 1（IDO1）是催化色氨酸氧化代谢的酶，它导致肿瘤微环境中的癌症免疫抑制。已经报道了几种靶向 IDO1 的化合物，epacadostat 对 IDO1 表现出很强的抑制活性，正在临床试验中进一步研究。然而，其药代动力学特征并不理想。epacadostat 在人体内的半衰期为 2.4 小时，在 III 期临床试验中的剂量为 50mg BID。为了克服 epacadostat 的缺点，通过改变 epacadostat 的代谢途径并增强抗肿瘤效力，进行了基于结构的药物设计来改善药代动力学特征。设计、合成了一系列带有侧链中环的 1,2,5-噁二唑-3-甲脒衍生物，并对其抗肿瘤活性进行了评价。它们中的大多数在酶促测定和过表达 hIDO1 的 HEK293T 细胞中对 hIDO1 表现出很强的活性。其中，化合物 23、25 和 26 对 hIDO1 表现出显著的抑制活性（IC = 108.7、178.1 和 139.1 nM），在表达 hIDO1 的 HEK293T 细胞中也有活性（细胞 IC = 19.88、68.59 和 57.76 nM）。此外，与 epacadostat 相比，化合物 25 具有更好的 PK 特性，半衰期更长（在 CD-1 小鼠中 t = 3.81 小时），口服生物利用度更高（F = 33.6%）。此外，与 epacadostat 相比，化合物 25 抑制 CT-26 同源异种移植瘤生长的效力相似，这使其值得进一步研究。
