Abstract
The discovery and optimisation of a novel series of potent and selective p38α inhibitors is described. Evaluating the structure-activity relationship of an aminoalkyl substituent at the 3 position of the 2(1H)-pyrazinone core, p38α potency was increased 20000-fold. The most advanced compound (25) demonstrated excellent in vivo properties suitable for an inhaled route of administration.
Keywords:
AZD6703; AZD7624; COPD; Inflammation; Kinases; P38α.
Copyright © 2020 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Inhalation
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Alkanes / chemistry
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Amines / chemistry
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Animals
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Anti-Inflammatory Agents / administration & dosage
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Anti-Inflammatory Agents / adverse effects
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Anti-Inflammatory Agents / chemical synthesis*
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Anti-Inflammatory Agents / pharmacokinetics
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Benzamides / pharmacology
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Dogs
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Drug Evaluation, Preclinical
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Humans
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Inflammation / drug therapy*
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Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
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Models, Molecular
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / adverse effects
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacokinetics
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Pulmonary Disease, Chronic Obstructive / drug therapy*
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Pyrazines / chemical synthesis*
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Pyrazines / pharmacology
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Quinazolines / pharmacology
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Rats
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Structure-Activity Relationship
Substances
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Alkanes
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Amines
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Anti-Inflammatory Agents
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Benzamides
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N-cyclopropyl-4-methyl-3-(6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl)benzamide
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Protein Kinase Inhibitors
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Pyrazines
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Quinazolines
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AZD7624
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Mitogen-Activated Protein Kinase 14