ipratropium and Pulmonary-Disease--Chronic-Obstructive

In this paper, we report the discovery of dual M

Topics: Animals; Cyclic Nucleotide Phosphodiesterases, Type 4; Dose-Response Relationship, Drug; Drug Discovery; Guinea Pigs; Male; Molecular Structure; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Inbred BN; Rats, Sprague-Dawley; Receptor, Muscarinic M3; Structure-Activity Relationship

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.

Topics: Adrenergic beta-2 Receptor Agonists; Animals; Biological Availability; Bronchoconstriction; Bronchodilator Agents; CHO Cells; Cricetulus; Dogs; Humans; Ipratropium; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Rats; Receptor, Muscarinic M3; Salmeterol Xinafoate; Tiotropium Bromide; Triazoles