Abstract
Interruption of TGFbeta signaling through inhibition of the TGFbetaR1 kinase domain may prove to have beneficial effect in both fibrotic and oncological diseases. Herein we describe the SAR of a novel series of TGFbetaR1 kinase inhibitors containing a pyrazolone core. Most TGFbetaR1 kinase inhibitors described to date contain a core five-membered ring bearing N as H-bond acceptor. Described herein is a novel strategy to replace the core structure with pyrazolone ring, in which the carbonyl group is designed as an H-bond acceptor to interact with catalytic Lys 232.
Copyright 2009 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Binding Sites
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Crystallography, X-Ray
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Mice
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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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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Pyrazolones / chemical synthesis
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Pyrazolones / chemistry*
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Pyrazolones / pharmacokinetics
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Rats
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
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Receptors, Transforming Growth Factor beta / metabolism
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Structure-Activity Relationship
Substances
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Protein Kinase Inhibitors
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Pyrazolones
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Receptors, Transforming Growth Factor beta
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pyrazolone
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
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Tgfbr1 protein, rat