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

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

  • ACS Med Chem Lett. 2019 Feb 21;10(3):383-388. doi: 10.1021/acsmedchemlett.9b00035.
Chunjian Liu 1,  James Lin 1,  Ryan Moslin 1,  John S Tokarski 1,  Jodi Muckelbauer 1,  ChiehYing Chang 1,  Jeffrey Tredup 1,  Dianlin Xie 1,  Hyunsoo Park 1,  Peng Li 1,  Dauh-Rurng Wu 1,  Joann Strnad 1,  Adriana Zupa-Fernandez 1,  Lihong Cheng 1,  Charu Chaudhry 1,  Jing Chen 1,  Cliff Chen 1,  Huadong Sun 1,  Paul Elzinga 1,  Celia D'arienzo 1,  Kathleen Gillooly 1,  Tracy L Taylor 1,  Kim W McIntyre 1,  Luisa Salter-Cid 1,  Louis J Lombardo 1,  Percy H Carter 1,  Nelly Aranibar 1,  James R Burke 1,  David S Weinstein 1
Affiliations

Affiliation

  • 1 Research & Development, Bristol-Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543, United States.
PMID: 30891145 DOI: 10.1021/acsmedchemlett.9b00035
Abstract

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 IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat Adjuvant arthritis model.

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