Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Bioorg Med Chem. 2019 Mar 1;27(5):790-799. doi: 10.1016/j.bmc.2019.01.019. Epub 2019 Jan 23.
Protein kinase C theta (PKCθ) plays a critical role in T cell signaling and has therapeutic potential for T cell-mediated diseases such as transplant rejection and rheumatoid arthritis. PKCθ inhibitors have emerged as effective immunomodulative agents for the prevention of transplant rejection. We previously reported that the 2,4-diamino-5-cyanopyrimidine derivative 2 was a potent PKCθ inhibitor; however, it exhibited CYP3A4 time-dependent inhibition (TDI). Here, we report the structural modification of compound 2 into 34 focusing on mitigating CYP3A4 TDI. Compound 34 exhibited potent in vitro activity with mitigated CYP3A4 TDI and efficacy in vivo transplant model.
蛋白激酶 C 理论（PKCθ）在 T 细胞信号转导中发挥着关键作用，对于 T 细胞介导的疾病（如移植排斥和类风湿性关节炎）具有治疗潜力。PKCθ 抑制剂已成为预防移植排斥的有效免疫调节剂。我们之前报道过，2,4-二氨基-5-氰基嘧啶衍生物 2 是一种有效的 PKCθ 抑制剂；然而，它表现出 CYP3A4 时间依赖性抑制（TDI）。在这里，我们将化合物 2 进行结构修饰，重点减轻 CYP3A4 TDI，得到化合物 34。化合物 34 表现出很强的体外活性，同时减轻了 CYP3A4 TDI，并且在体内移植模型中具有疗效。
