Identification of second-generation P2X3 antagonists for treatment of pain

A second-generation small molecule P2X3 receptor antagonist has been developed. The lead optimization strategy to address shortcomings of the first-generation preclinical lead compound is described herein. These studies were directed towards the identification and amelioration of preclinical hepatob...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2018-05, Vol.28 (8), p.1392-1396
Main Authors: Ginnetti, Anthony T., Paone, Daniel V., Stauffer, Shaun R., Potteiger, Craig M., Shaw, Anthony W., Deng, James, Mulhearn, James J., Nguyen, Diem N., Segerdell, Carolyn, Anquandah, Juliana, Calamari, Amy, Cheng, Gong, Leitl, Michael D., Liang, Annie, Moore, Eric, Panigel, Jacqueline, Urban, Mark, Wang, Jixin, Fillgrove, Kerry, Tang, Cuyue, Cook, Sean, Kane, Stefanie, Salvatore, Christopher A., Graham, Samuel L., Burgey, Christopher S.
Format: Article
Language:English
Subjects:
Analgesics - chemical synthesis
Analgesics - chemistry
Analgesics - pharmacokinetics
Analgesics - therapeutic use
Animals
Benzamides - chemical synthesis
Benzamides - chemistry
Benzamides - pharmacokinetics
Benzamides - therapeutic use
Dogs
Drug Design
Drug Interactions
Drug-drug interaction
Glucuronosyltransferase - antagonists & inhibitors
Half-Life
Hyperbilirubinemia - prevention & control
Molecular Structure
P2X3
Pain
Pain - drug therapy
Purinergic P2X Receptor Antagonists - chemical synthesis
Purinergic P2X Receptor Antagonists - chemistry
Purinergic P2X Receptor Antagonists - pharmacokinetics
Purinergic P2X Receptor Antagonists - therapeutic use
Purinergic receptor
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - pharmacokinetics
Pyridines - therapeutic use
Rats
Receptors, Purinergic P2X3 - metabolism
Stereoisomerism
Structure-Activity Relationship
UGT1A1
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Description
Summary:A second-generation small molecule P2X3 receptor antagonist has been developed. The lead optimization strategy to address shortcomings of the first-generation preclinical lead compound is described herein. These studies were directed towards the identification and amelioration of preclinical hepatobiliary findings, reducing potential for drug-drug interactions, and decreasing the projected human dose of the first-generation lead. [Display omitted] A second-generation small molecule P2X3 receptor antagonist has been developed. The lead optimization strategy to address shortcomings of the first-generation preclinical lead compound is described herein. These studies were directed towards the identification and amelioration of preclinical hepatobiliary findings, reducing potential for drug-drug interactions, and decreasing the projected human dose of the first-generation lead.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2018.02.039