title: Discovery of a muscarinic M3 receptor antagonist with high selectivity for M3 over M2 receptors among 2-[(1S,3S)-3-sulfonylaminocyclopentyl]phenylacetamide derivatives.
abstract: In the course of developing a metabolically stable M3 receptor antagonist from the prototype antagonist, J-104129 (1), introduction of certain substituents into the cyclopentane ring of 1 was found to be effective not only in improving metabolic stability but also in greatly enhancing the subtype selectivity. Among the cyclopentane analogues, sulfonamide derivatives (10f) and (10g) displayed 160- and 310-fold selectivity for M3 over M2 receptors, and both were significantly more selective than the prototype antagonist (120-fold). Subsequent derivatization of the sulfonamide series led to the highly selective M3 receptor antagonists (10h, 10i and 10j) with >490-fold selectivity for M3 over M2 receptors. Among them, p-nitrophenylsulfonamide (J-107320, 10h) exhibited 1100-fold selectivity for M3 receptors (Ki = 2.5 nM) over M2 receptors (Ki = 2800 nM) in the human muscarinic receptor binding assay using [3H]-NMS as a radio ligand.
authors.affiliation: Banzu Tsukuba Research Institute in collaboration with Merck Research Laboratories, Tsukuba, Ibaraki, Japan. mituyamr@banyu.co.jp
authors.forename: M
authors.initials: M
authors.lastname: Mitsuya
authors.forename: Y
authors.initials: Y
authors.lastname: Ogino
authors.forename: K
authors.initials: K
authors.lastname: Kawakami
authors.forename: M
authors.initials: M
authors.lastname: Uchiyama
authors.forename: T
authors.initials: T
authors.lastname: Kimura
authors.forename: T
authors.initials: T
authors.lastname: Numazawa
authors.forename: T
authors.initials: T
authors.lastname: Hasegawa
authors.forename: N
authors.initials: N
authors.lastname: Ohtake
authors.forename: K
authors.initials: K
authors.lastname: Noguchi
authors.forename: T
authors.initials: T
authors.lastname: Mase
mesh_terms: D000475:Alkenes / Q000737:chemistry / Q000494:pharmacology*; D003517:Cyclopentanes / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D018727:Muscarinic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects*
chemical_list: D000475:Alkenes; D003517:Cyclopentanes; C121300:J 104129; D018727:Muscarinic Antagonists; D010880:Piperidines; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic