Discovery of Novel Potent Muscarinic M 3 Receptor Antagonists with Proper Plasma Stability by Structural Recombination of Marketed M 3 Antagonists

The marketed long‐acting M 3 antagonists for treatment of chronic obstructive pulmonary disease have inappropriate plasma stability (either overstable or excessively unstable), which causes substantial systemic exposure or poor patient compliance. To discover novel M 3 antagonists with proper plasma stability, we synthesized and biologically evaluated a series of chiral quaternary ammonium salts of pyrrolidinol esters, which were designed by structural recombination of the marketed M 3 antagonists. As a result, two novel potent M 3 antagonists, ( R / S )‐3‐[2‐hydroxy‐2,2‐di(thiophen‐2‐yl)acetoxy]‐1,1‐dimethylpyrrolidinium bromides ( 1 a : K i =0.16 n m , IC 50 =0.38 n m , t 1/2 =9.34 min; 1 b : K i =0.32 n m , IC 50 =1.01 n m , t 1/2 =19.2 min) with proper plasma stability were identified, which (particularly 1 a ) hold great promise as clinical drug candidates to overcome the drawbacks caused by the inappropriate stability of the currently marketed M 3 antagonists. In addition, structure–activity relationship studies revealed that the R configuration of the pyrrolidinyl C3 atom was clearly better than the S configuration.