J-104129, a novel muscarinic M 3 receptor antagonist with high selectivity for M 3 over M 2 receptors

A new class of 4-acetamidopiperidine derivatives has been synthesized and investigated for human muscarinic receptor subtype selectivity. Introduction of a hydrocarbon chain of appropriate length into the piperidine nitrogen of the racemic N -(piperidin-4-yl)-2-cyclobutyl-2-hydroxy-2-phenylacetamide platform conferred up to 70-fold selectivity for human muscarinic M 3 receptors over M 2 receptors. Subsequent synthetic derivatizations resulted in highly potent M 3 receptor antagonists with selectivity greater than two orders of magnitude for M 3 over M 2 receptors, from which the analogue 4r was selected. Preparation of both enantiomers of 4r led to the identification of (2 R )- N -[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide (J-104129, (R)-4r ), which exhibited 120-fold selectivity for M 3 receptors ( K i =4.2 nM) over M 2 receptors ( K i =490 nM). In isolated rat trachea, (R)-4r potently and specifically antagonized acetylcholine (ACh)-induced responses with a K B value of 3.3 nM. The highly subtype-selective profile was also seen in isolated rat tissue assays (50-fold) and in anesthetized rats (>250-fold). Oral administration of J-104129 ( (R)-4r ) antagonized ACh-induced bronchoconstriction with an ED 50 value of 0.58 mg/kg in rats. Thus, J-104129 ( (R)-4r ) may effectively facilitate bronchodilation in the treatment of obstructive airway disease.