Discovery of potent and efficacious pyrrolopyridazines as dual JAK1/3 inhibitors.
John Hynes, Hong Wu, James Kempson, James J-W Duan, Zhonghui Lu, Bin Jiang, Sylwia Stachura, John S Tokarski, John S Sack, Javed A Khan, Jonathan S Lippy, Rosemary F Zhang, Sidney Pitt, Guoxiang Shen, Kate Gillooly, Kim McIntyre, Percy H Carter, Joel C Barrish, Steven G Nadler, Luisa M Salter-Cid, Aberra Fura, Gary L Schieven, William J Pitts, Stephen T Wrobleski
Author Information
John Hynes: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA. Electronic address: john.hynes@bms.com.
Hong Wu: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
James Kempson: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
James J-W Duan: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
Zhonghui Lu: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
Bin Jiang: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
Sylwia Stachura: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
John S Tokarski: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
John S Sack: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
Javed A Khan: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
Jonathan S Lippy: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
Rosemary F Zhang: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
Sidney Pitt: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
Guoxiang Shen: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
Kate Gillooly: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
Kim McIntyre: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
Percy H Carter: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
Joel C Barrish: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
Steven G Nadler: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
Luisa M Salter-Cid: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
Aberra Fura: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
Gary L Schieven: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
William J Pitts: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
Stephen T Wrobleski: Research and Development, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
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.
