Abstract
By applying conformational restrictions, we were able to discover highly potent 1,3-diaminopyrimidine based covalent inhibitors of BTK, such as 8a (IC50=3.76 nM), and providing useful information of its active conformation. We are developing these novel small molecule covalent inhibitors of BTK toward oral agents for Rheumatoid arthritis.
Keywords:
1,3-Diamino-pyrimidine; Bruton’s tyrosine kinase (BTK); Collagen-induced arthritis (CIA); Rheumatoid arthritis (RA).
Copyright © 2016 Elsevier Ltd. All rights reserved.
MeSH terms
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Agammaglobulinaemia Tyrosine Kinase
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Animals
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Arthritis, Rheumatoid / drug therapy*
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Arthritis, Rheumatoid / metabolism
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Dogs
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Dose-Response Relationship, Drug
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Humans
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Molecular Conformation
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / metabolism
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
Substances
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1,3-diaminopyrimidine
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Protein Kinase Inhibitors
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Pyrimidines
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Protein-Tyrosine Kinases
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Agammaglobulinaemia Tyrosine Kinase
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BTK protein, human