The transient receptor potential (TRP) family of ion channels is made up of non-selective cation channels that respond to a wide range of chemical and thermal stimuli. TRPM8, which is a member of the melastatin subfamily, is activated by cold temperatures (<25 �C) and antagonists of this channel have the potential to treat cold induced allodynia (pain caused by normally innocuous stimuli) and hyperalgesia (a prolonged or more intense pain response). However, TRPM8 has also been implicated in mammalian thermoregulation and antagonists have the potential to induce hypothermia in patients. In order to better understand this potential risk, we initiated a drug discovery program focused on delivery of a clinical tool compound. This talk will cover the identification and optimization of a series of TRPM8 antagonists which ultimately led to the discovery of a clinical tool compound PF-05105679. The screening campaign that was initiated, hit selection and hit to lead studies will be described, through to the SAR that led to the identification of the clinical tool. In addition, the clinical results for this compound will be discussed, including both clinical efficacy and its ability to affect thermoregulation processes in humans.

TRPM8 blockade and its role in cold pain signalling

247th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.