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

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.

SUBMITTER: Liu C

PROVIDER: S-EPMC6421589 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Liu Chunjian C Lin James J Moslin Ryan R Tokarski John S JS Muckelbauer Jodi J Chang ChiehYing C Tredup Jeffrey J Xie Dianlin D Park Hyunsoo H Li Peng P Wu Dauh-Rurng DR Strnad Joann J Zupa-Fernandez Adriana A Cheng Lihong L Chaudhry Charu C Chen Jing J Chen Cliff C Sun Huadong H Elzinga Paul P D'arienzo Celia C Gillooly Kathleen K Taylor Tracy L TL McIntyre Kim W KW Salter-Cid Luisa L Lombardo Louis J LJ Carter Percy H PH Aranibar Nelly N Burke James R JR Weinstein David S DS

ACS medicinal chemistry letters 20190221 3

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 ...[more]

PMID: 30891145

Dataset Information

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

Publications

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

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