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.
Anthony T Ginnetti  1 ,  Daniel V Paone  2 ,  Shaun R Stauffer  2 ,  Craig M Potteiger  2 ,  Anthony W Shaw  2 ,  James Deng  2 ,  James J Mulhearn  2 ,  Diem N Nguyen  2 ,  Carolyn Segerdell  2 ,  Juliana Anquandah  3 ,  Amy Calamari  3 ,  Gong Cheng  3 ,  Michael D Leitl  3 ,  Annie Liang  3 ,  Eric Moore  3 ,  Jacqueline Panigel  3 ,  Mark Urban  3 ,  Jixin Wang  3 ,  Kerry Fillgrove  4 ,  Cuyue Tang  4 ,  Sean Cook  3 ,  Stefanie Kane  3 ,  Christopher A Salvatore  3 ,  Samuel L Graham  2 ,  Christopher S Burgey  2
Affiliations
  • 1. Department of Medicinal Chemistry, MRL, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA. Electronic address: [email protected].
  • 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.
Products