title: Discovery of novel 2-((pyridin-3-yloxy)methyl)piperazines as α7 nicotinic acetylcholine receptor modulators for the treatment of inflammatory disorders.
abstract: Herein we report the design, synthesis, and structure-activity relationships for a new class of α7 nicotinic acetylcholine receptor (nAChR) modulators based on the 2-((pyridin-3-yloxy)methyl)piperazine scaffold. The oxazolo[4,5-b]pyridine, (R)-18, and 4-methoxyphenylurea, (R)-47, were identified as potent and selective modulators of the α7 nAChR with favorable in vitro safety profiles and good oral bioavailability in mouse. Both compounds were shown to significantly inhibit cellular infiltration in a murine model of allergic lung inflammation. Despite the structural and in vivo functional similarities in the compounds, only (R)-18 was shown to be an agonist. Compound (R)-47 demonstrated silent agonist activity. These data support the hypothesis that the anti-inflammatory activity of the α7 nAChR is mediated by a signal transduction pathway that is independent of ion current.
authors.affiliation: Critical Therapeutics, Inc. , 60 Westview Street, Lexington, Massachusetts 02421, United States.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Clark
authors.forename: Diana
authors.initials: D
authors.lastname: Lamppu
authors.forename: Lyn
authors.initials: L
authors.lastname: Libertine
authors.forename: Amy
authors.initials: A
authors.lastname: McDonough
authors.forename: Anjali
authors.initials: A
authors.lastname: Kumar
authors.forename: Greg
authors.initials: G
authors.lastname: LaRosa
authors.forename: Roger
authors.initials: R
authors.lastname: Rush
authors.forename: Daniel
authors.initials: D
authors.lastname: Elbaum
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D055808:Drug Discovery; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D016716:PC12 Cells; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*
chemical_list: D000893:Anti-Inflammatory Agents; D018722:Nicotinic Agonists; D010879:Piperazines; D064569:alpha7 Nicotinic Acetylcholine Receptor