Piperazine squaric acid diamides, a novel class of allosteric P2X7 receptor antagonists
| Autor: | Marius Patberg, Natalia V. Ortiz Zacarías, Oliver Koch, Anna Junker, Lucia Michetti, Laura H. Heitman, Cas van der Horst, Andreas Isaak, Laura Vinnenberg, Petra Hundehege, Lucie Grey, Thomas Budde, Friederike Füsser, Janine Schulte |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Purinergic P2X Receptor Antagonists
Allosteric regulation Squaric acid Plasma protein binding Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Tumor Cells Cultured Humans Piperazine Central element Allosteric ADME Diamide Pharmacology Dose-Response Relationship Drug Molecular Structure Organic Chemistry Purinergic receptor P2X General Medicine HEK293 Cells chemistry Biochemistry Receptors Purinergic P2X Docking (molecular) P2X7 receptor Antagonists Cyclobutanes |
| Zdroj: | European Journal of Medicinal Chemistry European Journal of Medicinal Chemistry, 226 |
| Popis: | The P2X7 receptor (P2X7R) stands out among the purinergic receptors due to its strong involvement in the regulation of tumor growth and metastasis formation as well as in innate immune responses and afferent signal transmission. Numerous studies have pointed out the beneficial effects of P2X7R antagonism for the treatment of a variety of cancer types, inflammatory diseases, and chronic pain. Herein we describe the development of novel P2X7R antagonists, incorporating piperazine squaric diamides as a central element. Besides improving the antagonists' potency from pIC50 values of 5.7-7.6, ADME properties (logD7.4 value, plasma protein binding, in vitro metabolic stability) of the generated compounds were investigated and optimized to provide novel P2X7R antagonists with drug-like properties. Furthermore, docking studies revealed the antagonists binding to the allosteric binding pocket in two distinct binding poses, depending on the substitution of the central piperazine moiety. |
| Databáze: | OpenAIRE |
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