Identification of second-generation P2X3 antagonists for treatment of pain

Anthony T Ginnetti; Daniel V Paone; Shaun R Stauffer; Craig M Potteiger; Anthony W Shaw; James Deng; James J Mulhearn; Diem N Nguyen; Carolyn Segerdell; Juliana Anquandah; Amy Calamari; Gong Cheng; Michael D Leitl; Annie Liang; Eric Moore; Jacqueline Panigel; Mark Urban; Jixin Wang; Kerry Fillgrove; Cuyue Tang; Sean Cook; Stefanie Kane; Christopher A Salvatore; Samuel L Graham; Christopher S Burgey

doi:10.1016/j.bmcl.2018.02.039

Identification of second-generation P2X3 antagonists for treatment of pain

Bioorg Med Chem Lett. 2018 May 1;28(8):1392-1396. doi: 10.1016/j.bmcl.2018.02.039. Epub 2018 Feb 21.

Authors

Anthony T Ginnetti¹, Daniel V Paone², Shaun R Stauffer², Craig M Potteiger², Anthony W Shaw², James Deng², James J Mulhearn², Diem N Nguyen², Carolyn Segerdell², Juliana Anquandah³, Amy Calamari³, Gong Cheng³, Michael D Leitl³, Annie Liang³, Eric Moore³, Jacqueline Panigel³, Mark Urban³, Jixin Wang³, Kerry Fillgrove⁴, Cuyue Tang⁴, Sean Cook³, Stefanie Kane³, Christopher A Salvatore³, Samuel L Graham², Christopher S Burgey²

Affiliations

¹ Department of Medicinal Chemistry, MRL, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA. Electronic address: anthony_ginnetti@merck.com.
² Department of Medicinal Chemistry, MRL, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
³ Department of Pain Research, MRL, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
⁴ Department of Drug Metabolism, MRL, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.

PMID: 29548573
DOI: 10.1016/j.bmcl.2018.02.039

Abstract

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.

Keywords: Drug-drug interaction; P2X3; Pain; Purinergic receptor; UGT1A1.

MeSH terms

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
Glucuronosyltransferase / antagonists & inhibitors
Half-Life
Hyperbilirubinemia / prevention & control
Molecular Structure
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*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacokinetics
Pyridines / therapeutic use*
Rats
Receptors, Purinergic P2X3 / metabolism*
Stereoisomerism
Structure-Activity Relationship

Substances

Analgesics
Benzamides
Purinergic P2X Receptor Antagonists
Pyridines
Receptors, Purinergic P2X3
Ugt1a1 protein, rat
Glucuronosyltransferase