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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Vydané v:	Bioorganic & medicinal chemistry letters Ročník 25; číslo 22; s. 5121 - 5126
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	England Elsevier Ltd 15.11.2015
Predmet:	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
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Shrnutí:	[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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405 1464-3405
DOI:	10.1016/j.bmcl.2015.10.008