Discovery of Novel 2-((Pyridin-3-yloxy)methyl)piperazines as α7 Nicotinic Acetylcholine Receptor Modulators for the Treatment of Inflammatory Disorders
| Autor: | Anjali Kumar, Amy McDonough, Roger B. Clark, Lyn Libertine, Greg LaRosa, Roger Rush, Daniel Elbaum, Diana Lamppu |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Agonist alpha7 Nicotinic Acetylcholine Receptor medicine.drug_class Anti-Inflammatory Agents Inflammation Pharmacology PC12 Cells Piperazines Mice Structure-Activity Relationship chemistry.chemical_compound In vivo Drug Discovery medicine Animals Nicotinic Agonists Mice Inbred BALB C Chemistry medicine.disease In vitro Rats Bioavailability Cellular infiltration Piperazine Biochemistry Molecular Medicine Signal transduction medicine.symptom |
| Zdroj: | Journal of Medicinal Chemistry. 57:3966-3983 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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