2. Academic Validation
  3. Discovery of potent and efficacious pyrrolopyridazines as dual JAK1/3 inhibitors

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

  • Bioorg Med Chem Lett. 2017 Jul 15;27(14):3101-3106. doi: 10.1016/j.bmcl.2017.05.043.
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

Affiliations

  • 1 Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA. Electronic address: [email protected].
  • 2 Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
PMID: 28539220 DOI: 10.1016/j.bmcl.2017.05.043
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.

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