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.
Keywords:
CIA efficacy; JAK inhibitor; JAK1/3; Pyrrolopyridazine.
Copyright © 2017 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Binding Sites
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Catalytic Domain
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Cell Line
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Crystallography, X-Ray
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Disease Models, Animal
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Drug Evaluation, Preclinical
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Half-Life
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Humans
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Inflammation / prevention & control
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Inhibitory Concentration 50
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Janus Kinase 1 / antagonists & inhibitors*
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Janus Kinase 1 / metabolism
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Janus Kinase 2 / antagonists & inhibitors
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Janus Kinase 2 / metabolism
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Janus Kinase 3 / antagonists & inhibitors*
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Janus Kinase 3 / metabolism
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Mice
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Mice, Inbred BALB C
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Molecular Conformation
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Molecular Dynamics Simulation
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Pyridazines / chemical synthesis
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Pyridazines / chemistry*
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Pyridazines / pharmacokinetics
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Pyrroles / chemical synthesis
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Pyrroles / chemistry*
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Pyrroles / pharmacokinetics
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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TYK2 Kinase / antagonists & inhibitors
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TYK2 Kinase / metabolism
Substances
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Protein Kinase Inhibitors
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Pyridazines
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Pyrroles
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Pyrrolopyridazine
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Janus Kinase 1
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Janus Kinase 2
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Janus Kinase 3
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TYK2 Kinase