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Discovery of potent and efficacious pyrrolopyridazines as dual JAK1/3 inhibitors
- Source :
- Bioorganicmedicinal chemistry letters. 27(14)
- Publication Year :
- 2017
-
Abstract
- A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.
- Subjects :
- 0301 basic medicine
Clinical Biochemistry
Drug Evaluation, Preclinical
Molecular Conformation
Pharmaceutical Science
Pharmacology
Crystallography, X-Ray
01 natural sciences
Biochemistry
Rats, Sprague-Dawley
chemistry.chemical_compound
Mice
Catalytic Domain
Drug Discovery
Mice, Inbred BALB C
biology
Chemistry
Translation (biology)
Pyridazines
Tyrosine kinase 2
Molecular Medicine
Half-Life
hERG
Molecular Dynamics Simulation
Pyrrolopyridazine
Cell Line
03 medical and health sciences
Inhibitory Concentration 50
Structure-Activity Relationship
In vivo
Potency
Animals
Humans
Pyrroles
Molecular Biology
Protein Kinase Inhibitors
Inflammation
TYK2 Kinase
Binding Sites
010405 organic chemistry
Aryl
Organic Chemistry
Janus Kinase 3
Janus Kinase 1
Janus Kinase 2
0104 chemical sciences
Rats
Disease Models, Animal
030104 developmental biology
Murine model
biology.protein
Subjects
Details
- ISSN :
- 14643405
- Volume :
- 27
- Issue :
- 14
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry letters
- Accession number :
- edsair.doi.dedup.....253daa677cbcba359ab77a6e70a14d27