6NSL

Identification of Imidazo[1,2-b]pyridazine Derivatives as Potent, Selective, and Orally Active Tyk2 JH2 Inhibitors.

Liu, C., Lin, J., Moslin, R., Tokarski, J.S., Muckelbauer, J., Chang, C., Tredup, J., Xie, D., Park, H., Li, P., Wu, D.R., Strnad, J., Zupa-Fernandez, A., Cheng, L., Chaudhry, C., Chen, J., Chen, C., Sun, H., Elzinga, P., D'arienzo, C., Gillooly, K., Taylor, T.L., McIntyre, K.W., Salter-Cid, L., Lombardo, L.J., Carter, P.H., Aranibar, N., Burke, J.R., Weinstein, D.S.

(2019) ACS Med Chem Lett 10: 383-388

• PubMed: 30891145 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1021/acsmedchemlett.9b00035
• Primary Citation of Related Structures:  
  6NSL


• PubMed Abstract: 
  

  In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo- N 1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2- b ]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure-activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor 6 , which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.

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Organizational Affiliation: 

Research & Development, Bristol-Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543, United States.