Molecular hybridization yields triazole bronchodilators for the treatment of COPD

[Display omitted] 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 usi...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters Vol. 25; no. 22; pp. 5121 - 5126
Main Authors: Jones, Lyn H., Burrows, Jane, Feeder, Neil, Glossop, Paul, James, Kim, Jones, Rhys M., Kenyon, Amy S., Patel, Sheena, Roberts, Dannielle F., Selby, Matthew D., Strang, Ross S., Stuart, Emilio F., Trevethick, Michael A., Watson, Jessica, Wright, Karen N., Clarke, Nick
Format: Journal Article
Language:English
Published: England Elsevier Ltd 15.11.2015
Subjects:
Adrenergic beta-2 Receptor Agonists - chemical synthesis
Adrenergic beta-2 Receptor Agonists - pharmacokinetics
Adrenergic beta-2 Receptor Agonists - pharmacology
Animals
Bifunctional
Biological Availability
Bronchoconstriction - drug effects
Bronchodilator
Bronchodilator Agents - chemical synthesis
Bronchodilator Agents - pharmacokinetics
Bronchodilator Agents - pharmacology
CHO Cells
COPD
Cricetulus
Dogs
Humans
Inhalation by design
Ipratropium - pharmacology
MABA
Muscarinic Antagonists - chemical synthesis
Muscarinic Antagonists - pharmacokinetics
Muscarinic Antagonists - pharmacology
Pulmonary Disease, Chronic Obstructive - drug therapy
Rats
Receptor, Muscarinic M3 - antagonists & inhibitors
Salmeterol Xinafoate - pharmacology
Tiotropium Bromide - pharmacology
Triazoles - chemical synthesis
Triazoles - pharmacokinetics
Triazoles - pharmacology
MABA
Bifunctional
Inhalation by design
Bronchodilator
COPD
ISSN:0960-894X, 1464-3405, 1464-3405
Online Access:Get full text
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Summary:[Display omitted] 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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:0960-894X
1464-3405
1464-3405
DOI:10.1016/j.bmcl.2015.10.008