Abstract
Synthesis and SAR of a series of 7-azaindoles as Orai channel inhibitors showing good potency inhibiting IL-2 production in Jurkat cells is described. Compound 14d displaying best pharmacokinetic properties was further characterized in a model of allergen induced asthma showing inhibition in the number of eosinophils in BALF. High lipophilicity remains as one of the main challenges for this class of compounds.
Keywords:
CRAC channel; IL-2 inhibitors; LAD2; OVA model; Orai inhibitors.
Copyright © 2015 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Asthma
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Aza Compounds / chemistry
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Calcium Channel Blockers / chemistry*
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Calcium Channel Blockers / pharmacokinetics
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Calcium Channel Blockers / therapeutic use
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Calcium Channels / chemistry*
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Calcium Channels / metabolism
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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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Hypersensitivity / drug therapy
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Hypersensitivity / immunology
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Indoles / chemistry*
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Indoles / pharmacokinetics
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Indoles / therapeutic use
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Interleukin-2 / blood
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Interleukin-2 / metabolism
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Jurkat Cells
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Microsomes / metabolism
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Models, Biological
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Ovalbumin / immunology
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Protein Binding
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Pyridines / chemistry*
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Pyridines / pharmacokinetics
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Pyridines / therapeutic use
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Pyrroles / chemistry*
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Pyrroles / pharmacokinetics
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Pyrroles / therapeutic use
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Rats
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Structure-Activity Relationship
Substances
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Aza Compounds
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Calcium Channel Blockers
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Calcium Channels
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Indoles
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Interleukin-2
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Pyridines
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Pyrroles
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Ovalbumin