ABSTRACT
The P2X3 receptor is an attractive target for the treatment of pain and chronic coughing, and thus P2X3 antagonists have been developed as new therapeutic drugs. We previously reported selective P2X3 receptor antagonists by derivatization of hit compound 1. As a result, we identified hit compound 3, the structure of which was similar to hit compound 1. On the basis of SAR studies of hit compound 1, we modified hit compound 3 and compound 42 was identified as having analgesic efficacy by oral administration.
Subject(s)
Purinergic P2X Receptor Antagonists/chemistry , Purinergic P2X Receptor Antagonists/pharmacology , Pyrazolones/chemistry , Pyrazolones/pharmacology , Receptors, Purinergic P2X3/metabolism , Drug Discovery , Humans , Molecular Docking Simulation , Pyrroles/chemistry , Pyrroles/pharmacology , Receptors, Purinergic P2X3/chemistry , Structure-Activity RelationshipABSTRACT
Some P2X3 receptor antagonists have been developed as new therapeutic drugs for pain. We discovered a novel chemotype of P2X3 receptor antagonists with a pyrrolinone skeleton. Because of SAR studies to improve bioavailability of lead compound 2, compound (R)-24 was identified, which showed an analgesic effect against neuropathic pain by oral administration. We constructed a human P2X3 homology model as a template for the zebrafish P2X4 receptor, which agreed with SAR studies of pyrrolinone derivatives.
Subject(s)
Purinergic P2X Receptor Antagonists/pharmacology , Pyrroles/pharmacology , Receptors, Purinergic P2X3/drug effects , Administration, Oral , Biological Availability , Drug Discovery , High-Throughput Screening Assays , Humans , Inhibitory Concentration 50 , Neuralgia/drug therapy , Purinergic P2X Receptor Antagonists/administration & dosage , Purinergic P2X Receptor Antagonists/pharmacokinetics , Purinergic P2X Receptor Antagonists/therapeutic use , Structure-Activity RelationshipABSTRACT
The P2X3 receptor is primarily expressed in the peripheral sensory nerves, and therefore, antagonists of this receptor may be useful for the treatment of chronic pain. Pyrrolinone derivatives have been identified as a novel class of P2X3 receptor antagonists. A lead structure with moderate activity was discovered through a high-throughput screening assay. A structure-activity study led to the discovery of several P2X3 receptor antagonists. Compound 34 showed potent and specific antagonistic activity and analgesic efficacy.
