Discovery of tricyclic dipyrrolopyridine derivatives as novel JAK inhibitors

  • Bioorg Med Chem. 2017 Oct 15;25(20):5311-5326. doi: 10.1016/j.bmc.2017.07.043.
Hiroaki Yamagishi  1 ,  Takayuki Inoue  2 ,  Yutaka Nakajima  2 ,  Jun Maeda  2 ,  Hiroaki Tominaga  2 ,  Hiroyuki Usuda  2 ,  Takeshi Hondo  2 ,  Ayako Moritomo  2 ,  Fumihiro Nakamori  2 ,  Misato Ito  2 ,  Koji Nakamura  2 ,  Hiroki Morio  2 ,  Yasuyuki Higashi  2 ,  Masamichi Inami  2 ,  Shohei Shirakami  3
Affiliations
  • 1. Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: [email protected].
  • 2. Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
  • 3. Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: [email protected].
PMID: 28789911 DOI: 10.1016/j.bmc.2017.07.043
Abstract

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.

Keywords
Autoimmune diseases; IL-2; Immunomodulator; Janus kinase inhibitor; Organ transplant rejection.