The discovery and preclinical characterization of 6-chloro- N -(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinoline-5-carboxamide based P2X7 antagonists
| Autor: | Alec D. Lebsack, Alan D. Wickenden, Sandra R. Chaplan, Qi Wang, Jason C. Rech, Love Christopher John, William A. Eckert, J. Guy Breitenbucher, Ludwig Paul Cooymans, Leenaerts Joseph Elisabeth, Anindya Bhattacharya, Bryan James Branstetter, Hong Ao |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Purinergic P2X Receptor Antagonists medicine.drug_class Stereochemistry Interleukin-1beta Clinical Biochemistry Analgesic Pharmaceutical Science Carboxamide Tactile Allodynia Biochemistry Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Drug Discovery medicine Animals Humans Molecular Biology Whole blood Trifluoromethyl Chemistry Organic Chemistry Quinoline 030104 developmental biology Quinolines Molecular Medicine 030217 neurology & neurosurgery Ex vivo Paw edema |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 26:4781-4784 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2016.08.029 |
| Popis: | The synthesis, SAR and preclinical characterization of a series of 6-chloro- N -(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinoline-5-carboxamide based P2X7 antagonists is described herein. The lead compounds are potent inhibitors in Ca 2+ flux and whole blood IL-1β P2X7 release assays at both human and mouse isoforms. Compound 1e showed a robust reduction of IL-1β release in a mouse ex vivo model with a 50 mg/kg oral dose. Evaluation of compound 1e in the mouse SNI tactile allodynia, carrageenan-induced paw edema or CIA models resulted in no analgesic or anti-inflammatory effects. |
| Databáze: | OpenAIRE |
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