Identification of novel muscarinic M3 selective antagonists with a conformationally restricted Hyp-Pro spacer

The identification of potent and selective muscarinic M3 antagonists that are based on the recently discovered triphenylpropioamide derivative, 1, and have a unique amino acid spacer group is described. The introduction of a hydroxyproline-proline group to the spacer site and the use of a propyl or cyclopropylmethyl group as the piperidine N-substituent led to the discovery of the novel M3 selective antagonists [8c, 8g; Ki<2 nM (M3), M1/M3>700-fold, M2/M3>180-fold], which have a more rigid structure than 1.