Molecular hybridization yields triazole bronchodilators for the treatment of COPD.

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.

• Authors: Lyn H Jones, Jane Burrows, Neil Feeder, Paul Glossop, Kim James, Rhys M Jones, Amy S Kenyon, Sheena Patel, Dannielle F Roberts, Matthew D Selby, Ross S Strang, Emilio F Stuart, Michael A Trevethick, Jessica Watson, Karen N Wright, Nick Clarke
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 25 Issue 22 Pg. 5121-6 (Nov 15 2015) ISSN: 1464-3405 [Electronic] England
• PMID: 26471092 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Adrenergic beta-2 Receptor Agonists
• Bronchodilator Agents
• Muscarinic Antagonists
• PF-04810097
• Receptor, Muscarinic M3
• Triazoles
• Salmeterol Xinafoate
• Ipratropium
• Tiotropium Bromide

Topics

• Adrenergic beta-2 Receptor Agonists (chemical synthesis, pharmacokinetics, pharmacology)
• Animals
• Biological Availability
• Bronchoconstriction (drug effects)
• Bronchodilator Agents (chemical synthesis, pharmacokinetics, pharmacology)
• CHO Cells
• Cricetulus
• Dogs
• Humans
• Ipratropium (pharmacology)
• Muscarinic Antagonists (chemical synthesis, pharmacokinetics, pharmacology)
• Pulmonary Disease, Chronic Obstructive (drug therapy)
• Rats
• Receptor, Muscarinic M3 (antagonists & inhibitors)
• Salmeterol Xinafoate (pharmacology)
• Tiotropium Bromide (pharmacology)
• Triazoles (chemical synthesis, pharmacokinetics, pharmacology)