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Design, synthesis, and biological evaluation of 1,2,5-oxadiazole-3-carboximidamide derivatives as novel indoleamine-2,3-dioxygenase 1 inhibitors.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-01-11 , DOI: 10.1016/j.ejmech.2020.112059
Xiaohan Song 1 , Pu Sun 2 , Jiang Wang 1 , Wei Guo 2 , Yi Wang 3 , Ling-Hua Meng 2 , Hong Liu 1
Affiliation  

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 (IC50 = 108.7, 178.1 and 139.1 nM respectively) and in HEK293T cells expressing hIDO1 (cellular IC50 = 19.88, 68.59 and 57.76 nM respectively). Moreover, compound 25 displayed improved PK property with longer half-life (t1/2 = 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.

中文翻译:

设计,合成和生物学评估1,2,5-恶二唑-3-羧酰亚胺酰胺衍生物作为新型吲哚胺-2,3-二加氧酶1抑制剂。

吲哚胺2,3-双加氧酶1(IDO1)是催化色氨酸氧化代谢的酶,可解释肿瘤微环境中的癌症免疫抑制作用。已经报道了几种靶向IDO1的化合物,依帕多司他显示出对IDO1的强抑制活性,这在临床研究中得到了进一步的研究。但是,其药代动力学特征并不令人满意。依帕卡司他的半衰期在人类中为2.4小时,在III期临床试验中剂量为50 mg BID。为了克服依帕克司他的缺点,进行了基于结构的药物设计,以通过改变依帕克司他的代谢途径来改善药代动力学并增强抗肿瘤效力。设计,合成了一系列在侧链具有循环的1,2,5-恶二唑-3-羧酰亚胺酰胺衍生物,并对它们的抗肿瘤活性进行生物学评估。它们中的大多数在酶促测定和过表达hIDO1的HEK293T细胞中均表现出针对hIDO1的有效活性。其中,化合物23、25和26对hIDO1(分别为IC50分别为108.7、178.1和139.1 nM)和表达hIDO1的HEK293T细胞(细胞IC50分别为19.88、68.59和57.76 nM)显示出显着的抑制活性。此外,与依帕多司他相比,化合物25表现出改善的PK特性,具有更长的半衰期(CD-1小鼠中的t1 / 2 = 3.81 h)和更好的口服生物利用度(F = 33.6%)。此外,与依帕多司他相比,化合物25表现出相似的抑制CT-26同基因异种移植物生长的能力,因此有理由进一步研究。它们中的大多数在酶促测定和过表达hIDO1的HEK293T细胞中均表现出针对hIDO1的有效活性。其中,化合物23、25和26对hIDO1(分别为IC50分别为108.7、178.1和139.1 nM)和表达hIDO1的HEK293T细胞(细胞IC50分别为19.88、68.59和57.76 nM)显示出显着的抑制活性。此外,与依帕多司他相比,化合物25表现出改善的PK特性,具有更长的半衰期(CD-1小鼠中的t1 / 2 = 3.81 h)和更好的口服生物利用度(F = 33.6%)。此外,与依帕多司他相比,化合物25表现出相似的抑制CT-26同基因异种移植物生长的能力,因此有理由进一步研究。它们中的大多数在酶促测定和过表达hIDO1的HEK293T细胞中均表现出针对hIDO1的有效活性。其中,化合物23、25和26对hIDO1(分别为IC50分别为108.7、178.1和139.1 nM)和表达hIDO1的HEK293T细胞(细胞IC50分别为19.88、68.59和57.76 nM)显示出显着的抑制活性。此外,与依帕多司他相比,化合物25表现出改善的PK特性,具有更长的半衰期(CD-1小鼠中的t1 / 2 = 3.81 h)和更好的口服生物利用度(F = 33.6%)。此外,与依帕多司他相比,化合物25表现出相似的抑制CT-26同基因异种移植物生长的能力,因此有理由进一步研究。分别为1 nM)和表达hIDO1的HEK293T细胞(细胞IC50分别为19.88、68.59和57.76 nM)。此外,与依帕多司他相比,化合物25表现出改善的PK特性,具有更长的半衰期(CD-1小鼠中的t1 / 2 = 3.81 h)和更好的口服生物利用度(F = 33.6%)。此外,与依帕多司他相比,化合物25表现出相似的抑制CT-26同基因异种移植物生长的能力,因此有理由进一步研究。分别为1 nM)和表达hIDO1的HEK293T细胞(细胞IC50分别为19.88、68.59和57.76 nM)。此外,与依帕多司他相比,化合物25表现出改善的PK特性,具有更长的半衰期(CD-1小鼠中的t1 / 2 = 3.81 h)和更好的口服生物利用度(F = 33.6%)。此外,与依帕多司他相比,化合物25表现出相似的抑制CT-26同基因异种移植物生长的能力,因此有理由进一步研究。
更新日期:2020-01-13
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