Abstract
TrpA1 is an ion channel involved in nociceptive and inflammatory pain. It is implicated in the detection of chemical irritants through covalent binding to a cysteine-rich intracellular region of the protein. While performing an HTS of the Pfizer chemical collection, a class of pyrimidines emerged as a non-reactive, non-covalently binding family of agonists of the rat and human TrpA1 channel. Given the issues identified with the reference agonist Mustard Oil (MO) in screening, a new, non-covalently binding agonist was optimized and proved to be a superior agent to MO for screening purposes. Compound 16a (PF-4840154) is a potent, selective agonist of the rat and human TrpA1 channel and elicited TrpA1-mediated nocifensive behaviour in mouse.
Original language | English |
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Pages (from-to) | 4857 - 4859 |
Number of pages | 3 |
Journal | BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS |
Volume | 21 |
Issue number | 16 |
DOIs | |
Publication status | Published - 15 Aug 2011 |
Keywords
- Animals
- Ankyrins
- Calcium Channels
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Drug Design
- Edema
- Humans
- Mice
- Mice, Knockout
- Molecular Structure
- Nerve Tissue Proteins
- Pain
- Piperazines
- Pyrimidines
- Rats
- Stereoisomerism
- Structure-Activity Relationship
- TRPC Cation Channels
- Transient Receptor Potential Channels