title: J-104129, a novel muscarinic M3 receptor antagonist with high selectivity for M3 over M2 receptors.
abstract: 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 M3 receptors over M2 receptors. Subsequent synthetic derivatizations resulted in highly potent M3 receptor antagonists with selectivity greater than two orders of magnitude for M3 over M2 receptors, from which the analogue 4r was selected. Preparation of both enantiomers of 4r led to the identification of (2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-cyclopentyl-2-hyd roxy-2-phenylacetamide (J-104129, (R)-4r), which exhibited 120-fold selectivity for M3 receptors (Ki = 4.2 nM) over M2 receptors (Ki = 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 ED50 value of 0.58 mg/kg in rats. Thus, J-104129 ((R)-4r) may effectively facilitate bronchodilation in the treatment of obstructive airway disease.
authors.affiliation: Banyu Tsukuba Research Institute in collaboration with Merck Research Laboratories, Ibaraki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Mitsuya
authors.forename: T
authors.initials: T
authors.lastname: Mase
authors.forename: Y
authors.initials: Y
authors.lastname: Tsuchiya
authors.forename: K
authors.initials: K
authors.lastname: Kawakami
authors.forename: H
authors.initials: H
authors.lastname: Hattori
authors.forename: K
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Ogino
authors.forename: T
authors.initials: T
authors.lastname: Fujikawa
authors.forename: A
authors.initials: A
authors.lastname: Satoh
authors.forename: T
authors.initials: T
authors.lastname: Kimura
authors.forename: K
authors.initials: K
authors.lastname: Noguchi
authors.forename: N
authors.initials: N
authors.lastname: Ohtake
authors.forename: K
authors.initials: K
authors.lastname: Tomimoto
mesh_terms: D000475:Alkenes / Q000138:chemical synthesis / Q000378:metabolism*; D000818:Animals; D001993:Bronchodilator Agents / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D008297:Male; D018727:Muscarinic Antagonists / Q000378:metabolism*; D010880:Piperidines / Q000138:chemical synthesis / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014132:Trachea / Q000378:metabolism
chemical_list: D000475:Alkenes; D001993:Bronchodilator Agents; C121300:J 104129; D018727:Muscarinic Antagonists; D010880:Piperidines; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D011994:Recombinant Proteins