title: Identification of novel muscarinic M(3) selective antagonists with a conformationally restricted Hyp-Pro spacer.
abstract: 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.
authors.affiliation: Banyu Tsukuba Research Institute in collaboration with Merck Research Laboratories, Okubo-3, Ibaraki, Japan. oowadayf@banyu.co.jp
authors.forename: Yufu
authors.initials: Y
authors.lastname: Sagara
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Kimura
authors.forename: Toru
authors.initials: T
authors.lastname: Fujikawa
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Noguchi
authors.forename: Norikazu
authors.initials: N
authors.lastname: Ohtake
mesh_terms: D000577:Amides; D020650:Combinatorial Chemistry Techniques; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006909:Hydroxyproline; D008968:Molecular Conformation; D018727:Muscarinic Antagonists / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D018727:Muscarinic Antagonists; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; C034666:propionamide; D006909:Hydroxyproline