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

doi:10.1021/acsmedchemlett.9b00035

Paper

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

Published Feb 21, 2019 · Chunjian Liu, James Lin, R. Moslin

ACS medicinal chemistry letters

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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.

Study Snapshot

Imidazo[1,2-b]pyridazine derivatives show improved metabolic stability and potency as Tyk2 JH2 inhibitors, with potential for oral administration in treating inflammatory diseases.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Paper

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

References

Identification of imidazo[1,2-b]pyridazine TYK2 pseudokinase ligands as potent and selective allosteric inhibitors of TYK2 signalling.

The JH2-selective TYK2 inhibitor 29 shows promising systemic exposures after oral dosing in mice, with potential for treating immuno-inflammatory diseases.

Structure-Based Design and Synthesis of 3-Amino-1,5-dihydro-4H-pyrazolopyridin-4-one Derivatives as Tyrosine Kinase 2 Inhibitors.

The novel TYK2 inhibitors, 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one derivatives, show unique cytokine selectivity and potential for clinical development against IL-23-induced IL-22 production.

Upcoming biological therapies in systemic lupus erythematosus.

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Targeting Interferons in Systemic Lupus Erythematosus: Current and Future Prospects

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Tyrosine Kinase 2-mediated Signal Transduction in T Lymphocytes Is Blocked by Pharmacological Stabilization of Its Pseudokinase Domain*

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Citations

Tyrosine kinase 2 inhibitors: Synthesis and applications in the treatment of autoimmune diseases.

TYK2 inhibitors show potential in treating autoimmune diseases with reduced side effects and improved therapeutic outcomes.

TYK2 Protein Expression and Its Potential as a Tissue-Based Biomarker for the Diagnosis of Colorectal Cancer

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Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics

This review aims to enhance understanding of JAK specificity and develop effective and selective inhibitors for cancer therapy, improving cancer prognosis.

Allosteric TYK2 inhibition: redefining autoimmune disease therapy beyond JAK1-3 inhibitors.

Deucravacitinib, a first-in-class allosteric TYK2 inhibitor, offers high functional selectivity and efficacy-safety for treating autoimmune diseases, with potential for exploration in other autoimmune diseases.

Progress on the Pharmacological Targeting of Janus Pseudokinases.

Targeting JH2 domains in Janus kinases may offer a safer approach for treating diseases like plaque psoriasis without the adverse effects associated with targeting the adjacent JH1 domain.