Abstract
A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a β2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.
Keywords:
Bifunctional; Bronchodilator; COPD; Inhalation by design; MABA.
Copyright © 2015 Elsevier Ltd. All rights reserved.
MeSH terms
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Adrenergic beta-2 Receptor Agonists / chemical synthesis*
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Adrenergic beta-2 Receptor Agonists / pharmacokinetics
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Adrenergic beta-2 Receptor Agonists / pharmacology
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Animals
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Biological Availability
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Bronchoconstriction / drug effects
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Bronchodilator Agents / chemical synthesis*
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Bronchodilator Agents / pharmacokinetics
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Bronchodilator Agents / pharmacology
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CHO Cells
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Cricetulus
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Dogs
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Humans
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Ipratropium / pharmacology
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Muscarinic Antagonists / chemical synthesis*
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Muscarinic Antagonists / pharmacokinetics
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Muscarinic Antagonists / pharmacology
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Pulmonary Disease, Chronic Obstructive / drug therapy*
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Rats
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Receptor, Muscarinic M3 / antagonists & inhibitors
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Salmeterol Xinafoate / pharmacology
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Tiotropium Bromide / pharmacology
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Triazoles / chemical synthesis*
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Triazoles / pharmacokinetics
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Triazoles / pharmacology
Substances
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Adrenergic beta-2 Receptor Agonists
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Bronchodilator Agents
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Muscarinic Antagonists
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PF-04810097
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Receptor, Muscarinic M3
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Triazoles
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Salmeterol Xinafoate
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Ipratropium
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Tiotropium Bromide