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


Journal Article

© 2019 American Chemical Society. In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-N1-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 IFNÎγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.

Full Text

Cited Authors

  • Liu, C; Lin, J; Moslin, R; Tokarski, JS; Muckelbauer, J; Chang, CY; Tredup, J; Xie, D; Park, H; Li, P; Wu, DR; Strnad, J; Zupa-Fernandez, A; Cheng, L; Chaudhry, C; Chen, J; Chen, C; Sun, H; Elzinga, P; D'Arienzo, C; Gillooly, K; Taylor, TL; McIntyre, KW; Salter-Cid, L; Lombardo, LJ; Carter, PH; Aranibar, N; Burke, JR; Weinstein, DS

Published Date

  • March 14, 2019

Published In

Volume / Issue

  • 10 / 3

Start / End Page

  • 383 - 388

Electronic International Standard Serial Number (EISSN)

  • 1948-5875

Digital Object Identifier (DOI)

  • 10.1021/acsmedchemlett.9b00035

Citation Source

  • Scopus