Identification of a novel 4-aminomethylpiperidine class of M3 muscarinic receptor antagonists and structural insight into their M3 selectivity.

Identification of a novel class of potent and highly selective M(3) muscarinic antagonists is described. First, the structure-activity relationship in the cationic amine core of our previously reported triphenylpropionamide class of M(3) selective antagonists was explored by a small diamine library constructed in solid phase. This led to the identification of M(3) antagonists with a novel piperidine pharmacophore and significantly improved subtype selectivity from a previously reported class.

Discovery of 2-aminothiazole-4-carboxamides, a novel class of muscarinic M(3) selective antagonists, through solution-phase parallel synthesis.

Synthesis and structure-activity relationship of a new class of muscarinic M(3) selective antagonists were described. In the course of searching for a muscarinic M(3) antagonist with a structure distinct from those of the 2-(4,4-difluorocyclopentyl)-2-phenylacetamide derivatives, we identified a thiazole-4-carboxamide derivative (1) as a lead compound in our in-house chemical collection. Since this compound (1) showed relatively low binding affinity (K(i)=140 nM) for M(3) receptors in the human binding assays, we tried to improve its potency and selectivity for M(3) over M(1) and M(2) receptors by derivatization of 1 through a combinatorial approach.

Identification of novel muscarinic M(3) selective antagonists with a conformationally restricted Hyp-Pro spacer.

The identification of potent and selective muscarinic M(3) 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 M(3) selective antagonists [8c, 8g; K(i)<2 nM (M(3)), M(1)/M(3)>700-fold, M(2)/M(3)>180-fold], which have a more rigid structure than 1.

Cyclohexylmethylpiperidinyltriphenylpropioamide: a selective muscarinic M(3) antagonist discriminating against the other receptor subtypes.

To discover a highly selective M(3) antagonist, a combinatorial library was prepared. The library was designed to identify a novel structural class of M(3) antagonists by exploring the spatial arrangement of the pharmacophores in known M(3) antagonists. After the evaluation of 1000 library members, a potent M(3) antagonist, 14a (K(i) = 0.