Serentrix is developing compounds for multiple indications that involve TRPV1 receptors. NSAIDs (non-steroidal anti-inflammatory drugs), opiates and other analgesics are useful drugs for many patients, but exhibit dose-limiting side effects, inadequate tolerability profiles and diminished efficacy over time. Consequently, pain is often under treated.

TRPV1 is perhaps the most important signal integrator in sensory nociceptors, is well established as an intriguing novel target for the treatment of pain. Extensive preclinical profiling of small-molecule inhibitors of TRPV1 provides intriguing evidence that TRPV1 blockade can be a useful therapeutic approach for inflammatory, and possibly neuropathic pain.

TRPV1 antagonism represents one of several novel mechanistic approaches to pain relief that might qualify as the next-generation analgesic. But although most of the drugs in development target the inflammatory system and the propagation and transmission of signals to the spinal cord, TRPV1 antagonists target the key mediator of nociceptive transduction. Because of TRPV1’s integrative signaling properties in response to inflammatory stimuli, TRPV1 antagonists are predicted to inhibit the sensation of ongoing or burning pain (spontaneous pain) that is reported by patients suffering from chronic pain, therefore, offering an unprecedented advantage in selectively inhibiting painful signaling without mechanistic limitations.

TRPV1 receptor antagonists were developed for pain by multiple companies in early 2010, however most of these were discontinued due to side effects like hyperthermia and increase in heat pain perception threshold associated with them.  These 1st generation compounds were designed as broad-spectrum analgesics, polymodal TRPV1 antagonists.  They potently block all 3 modes (heat, protons and capsaicin) of TRPV1 activation.  Our compound, SER114, earlier named PHE377, is a next generation compound designed to create thermally neutral antagonists. It does that as it is a modality selective TRPV1 antagonist and has no potent effect on the proton activation mode, and thus has no effect on body temperature.  It has been shown to be better than several competitor compounds and in 35 subjects Phase 1 human clinical studies, no increase in body temperature was observed. We are developing this compound and a back-up compound for multiple indications.