The objective of this work was to discover a novel, long-acting muscarinic M(3) antagonist for the inhaled treatment of chronic obstructive pulmonary disease (COPD), with a potentially improved risk-benefit profile compared with current antimuscarinic agents. A series of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters were synthesized and evaluated. On the basis of its overall profile, (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide) emerged as a candidate for once-daily maintenance treatment of COPD. This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. Aclidinium bromide is currently in phase III development for maintenance treatment of patients with COPD.

We have designed, synthesized, and tested two small collections of potential tryptase inhibitors. The first library consists of diversely N-substituted 3-aminopiperidin-2-ones 6, and the second (compounds 7) was prepared by dimerising compounds 6 through the 3-amino function using diverse carbon chains. We have established efficient routes for obtaining 6 both in solution and on solid supports. We have also compared the dimerisation on-resin and in solution. Four of the compounds showed a high degree of tryptase inhibition at 1 microM, but none surpassed the tryptase inhibition activity of BABIM.