AI Article Synopsis
- Janus kinases (JAKs) are important for signaling in cytokine pathways and JAK inhibitors are helpful in preventing transplant rejection.
- A previously identified JAK inhibitor, compound 2, was limited by poor oral absorption and low membrane permeability.
- The modified compound 18a was developed to improve these properties, showing better in vitro activity, increased membrane permeability, and effective results in rat heart transplant models.
Article 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.
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| http://dx.doi.org/10.1016/j.bmc.2017.07.043 | DOI Listing |
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