title: Synthesis, binding affinity and structure-activity relationships of novel, selective and dual targeting CCR2 and CCR5 receptor antagonists.
abstract: CCR2 and CCR5 receptors play a key role in the development and progression of several inflammatory, cardiovascular and autoimmune diseases. Therefore, dual targeting of both receptors appeals as a promising strategy for the treatment of such complex, multifactorial disorders. Herein we report on the design, synthesis and biological evaluation of benzo[7]annulene- and [7]annulenothiophene-based selective and dual CCR2 and CCR5 receptor antagonists. Intermediates were designed in such a way that diversification could be introduced at the end of the synthesis. Starting from the lead compound TAK-779 (1), the quaternary ammonium moiety was exchanged by different non-charged moieties, the 4-methylphenyl moiety was extensively modified and the benzo[7]annulene core was replaced bioisosterically by the [7]annulenothiophene system. The naphthyl derivative 9h represents the most promising dual antagonist (Ki (CCR2) = 25 nM, IC50 (CCR5) = 17 nM), whereas the 6-isopropoxy-3-pyridyl and 4-methoxycarbonylphenyl derivatives 9k and 9r show more than 20-fold selectivity for the CCR2 (Ki = 19 nM) over the CCR5 receptor.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstr. 48, D-48149 Münster, Germany. wuensch@uni-muenster.de.
authors.forename: Anna
authors.initials: A
authors.lastname: Junker
authors.forename: Artur K
authors.initials: AK
authors.lastname: Kokornaczyk
authors.forename: Annelien J M
authors.initials: AJ
authors.lastname: Zweemer
authors.forename: Bastian
authors.initials: B
authors.lastname: Frehland
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Junichiro
authors.initials: J
authors.lastname: Yamaguchi
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Itami
authors.forename: Andreas
authors.initials: A
authors.lastname: Faust
authors.forename: Sven
authors.initials: S
authors.lastname: Hermann
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.forename: Michael
authors.initials: M
authors.lastname: Koch
authors.forename: Christina
authors.initials: C
authors.lastname: Weiss
authors.forename: Laura H
authors.initials: LH
authors.lastname: Heitman
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D065100:CCR5 Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D011084:Polycyclic Aromatic Hydrocarbons / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C000603418:(7)annulenothiophene; D065100:CCR5 Receptor Antagonists; D011084:Polycyclic Aromatic Hydrocarbons; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D013876:Thiophenes; C434863:corannulene