Yamagishi Hiroaki, Inoue Takayuki, Nakajima Yutaka, Maeda Jun, Tominaga Hiroaki, Usuda Hiroyuki, Hondo Takeshi, Moritomo Ayako, Nakamori Fumihiro, Ito Misato, Nakamura Koji, Morio Hiroki, Higashi Yasuyuki, Inami Masamichi, Shirakami Shohei
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. 2017 Oct 15;25(20):5311-5326. doi: 10.1016/j.bmc.2017.07.043. Epub 2017 Jul 27.
Janus kinases (JAKs) play a crucial role in cytokine mediated signal transduction. JAK inhibitors have emerged as effective immunomodulative agents for the prevention of transplant rejection. We previously reported that the tricyclic imidazo-pyrrolopyridinone 2 is a potent JAK inhibitor; however, it had poor oral absorption due to low membrane permeability. Here, we report the structural modification of compound 2 into the tricyclic dipyrrolopyridine 18a focusing on reduction of polar surface area (PSA), which exhibits potent in vitro activity, improved membrane permeability and good oral bioavailability. Compound 18a showed efficacy in rat heterotopic cardiac transplants model.
Janus激酶（JAKs）在细胞因子介导的信号转导中起关键作用。JAK抑制剂已成为预防移植排斥反应的有效免疫调节药物。我们之前报道过三环咪唑并吡咯并吡啶2是一种有效的JAK抑制剂；然而，由于膜通透性低，其口服吸收较差。在此，我们报道将化合物2结构修饰为三环二吡咯并吡啶18a，重点是降低极性表面积（PSA），该化合物具有强大的体外活性、改善的膜通透性和良好的口服生物利用度。化合物18a在大鼠异位心脏移植模型中显示出疗效。
