Abstract
We previously reported that a 3-pyridinecarbonitrile analog with a furan substituent at C-5 and a 4-methylindol-5-ylamino substituent at C-4, 1, was a potent inhibitor of PKCtheta (IC50=4.5 nM). Replacement of the C-5 furan ring of 1 with bicyclic heteroaryl rings, led to compounds with significantly improved potency against PKCtheta. Analog 6b with a 4-methylindol-5-ylamino group at C-4 and a 5-[(4-methylpiperazin-1-yl)methyl]-1-benzofuran-2-yl group at C-5 had an IC50 value of 0.28 nM for the inhibition of PKCtheta.
MeSH terms
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Aminopyridines / chemical synthesis
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Aminopyridines / chemistry*
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Aminopyridines / pharmacology
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Animals
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Benzofurans / chemical synthesis
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Benzofurans / chemistry
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Benzofurans / pharmacology
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Half-Life
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Humans
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Interleukin-2 / metabolism
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Isoenzymes / antagonists & inhibitors*
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Isoenzymes / metabolism
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Mice
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Microsomes, Liver / metabolism
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Nitriles / chemical synthesis
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Nitriles / chemistry*
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Nitriles / pharmacology
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Protein Kinase C / antagonists & inhibitors*
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Protein Kinase C / metabolism
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Protein Kinase C-theta
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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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Pyridines / chemical synthesis
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Pyridines / chemistry*
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Pyridines / pharmacology
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Rats
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
Substances
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Aminopyridines
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Benzofurans
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Interleukin-2
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Isoenzymes
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Nitriles
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Protein Kinase Inhibitors
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Pyridines
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PRKCQ protein, human
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Protein Kinase C
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Protein Kinase C-theta