New P2X3 receptor antagonists. Part 1: Discovery and optimization of tricyclic compounds
| Autor: | Attila Makó, Mónika Vastag, Sándor Kolok, Attila Cselenyák, Imre Bata, Bence Farkas, Gábor Szántó |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Purinergic P2X Receptor Antagonists Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science Pharmacology Biochemistry Inhibitory Concentration 50 Structure-Activity Relationship 03 medical and health sciences Adenosine Triphosphate 0302 clinical medicine Heterocyclic Compounds In vivo Microsomes Drug Discovery Humans Structure–activity relationship Receptor Molecular Biology Ion channel Mesylates chemistry.chemical_classification Chemistry Organic Chemistry Purinergic receptor Combinatorial chemistry body regions 030104 developmental biology Drug development Molecular Medicine Heterocyclic Compounds 3-Ring Receptors Purinergic P2X3 030217 neurology & neurosurgery Protein Binding Tricyclic |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 26:3896-3904 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2016.07.009 |
| Popis: | Purinergic P2X3 receptors are trimeric ligand-gated ion channels whose antagonism is an appealing yet challenging and not fully validated drug development idea. With the aim of identification of an orally active, potent human P2X3 receptor antagonist compound that can penetrate the central nervous system, the compound collection of Gedeon Richter was screened. A hit series of tricyclic compounds was subjected to a rapid, two-step optimization process focusing on increasing potency, improving metabolic stability and CNS penetrability. Attempts resulted in compound 65, a potential tool compound for testing P2X3 inhibitory effects in vivo. |
| Databáze: | OpenAIRE |
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