Optimization of a Novel Quinazolinone-Based Series of Transient Receptor Potential A1 (TRPA1) Antagonists Demonstrating Potent in Vivo Activity

J Med Chem. 2016 Mar 24;59(6):2794-809. doi: 10.1021/acs.jmedchem.6b00039. Epub 2016 Mar 4.


There has been significant interest in developing a transient receptor potential A1 (TRPA1) antagonist for the treatment of pain due to a wealth of data implicating its role in pain pathways. Despite this, identification of a potent small molecule tool possessing pharmacokinetic properties allowing for robust in vivo target coverage has been challenging. Here we describe the optimization of a potent, selective series of quinazolinone-based TRPA1 antagonists. High-throughput screening identified 4, which possessed promising potency and selectivity. A strategy focused on optimizing potency while increasing polarity in order to improve intrinsic clearance culminated with the discovery of purinone 27 (AM-0902), which is a potent, selective antagonist of TRPA1 with pharmacokinetic properties allowing for >30-fold coverage of the rat TRPA1 IC50 in vivo. Compound 27 demonstrated dose-dependent inhibition of AITC-induced flinching in rats, validating its utility as a tool for interrogating the role of TRPA1 in in vivo pain models.

MeSH terms

  • Animals
  • Biological Transport, Active
  • CHO Cells
  • Calcium Channels
  • Cricetulus
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • High-Throughput Screening Assays
  • Humans
  • In Vitro Techniques
  • Madin Darby Canine Kidney Cells
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Oxadiazoles / chemical synthesis*
  • Oxadiazoles / pharmacology*
  • Pain Measurement / drug effects
  • Purines / chemical synthesis*
  • Purines / pharmacology*
  • Quinazolines / chemical synthesis*
  • Quinazolines / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • TRPA1 Cation Channel
  • Transient Receptor Potential Channels / antagonists & inhibitors*


  • AM-0902
  • Calcium Channels
  • Nerve Tissue Proteins
  • Oxadiazoles
  • Purines
  • Quinazolines
  • TRPA1 Cation Channel
  • TRPA1 protein, human
  • Transient Receptor Potential Channels