Molecular hybridization yields triazole bronchodilators for the treatment of COPD.
Jones LH, Burrows J, Feeder N, Glossop P, James K, Jones RM, Kenyon AS, Patel S, Roberts DF, Selby MD, Strang RS, Stuart EF, Trevethick MA, Watson J, Wright KN, Clarke N.
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.