Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Jul 15;27(14):3101-3106.
doi: 10.1016/j.bmcl.2017.05.043. Epub 2017 May 15.

Discovery of potent and efficacious pyrrolopyridazines as dual JAK1/3 inhibitors

John Hynes Jr  1 , Hong Wu  2 , James Kempson  2 , James J-W Duan  2 , Zhonghui Lu  2 , Bin Jiang  2 , Sylwia Stachura  2 , John S Tokarski  2 , John S Sack  2 , Javed A Khan  2 , Jonathan S Lippy  2 , Rosemary F Zhang  2 , Sidney Pitt  2 , Guoxiang Shen  2 , Kate Gillooly  2 , Kim McIntyre  2 , Percy H Carter  2 , Joel C Barrish  2 , Steven G Nadler  2 , Luisa M Salter-Cid  2 , Aberra Fura  2 , Gary L Schieven  2 , William J Pitts  2 , Stephen T Wrobleski  2
Affiliations

Discovery of potent and efficacious pyrrolopyridazines as dual JAK1/3 inhibitors

John Hynes Jr et al. Bioorg Med Chem Lett. .

Abstract

A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.

Keywords: CIA efficacy; JAK inhibitor; JAK1/3; Pyrrolopyridazine.

PubMed Disclaimer

MeSH terms

LinkOut - more resources