Joris Vriens1, Jean-Christophe Vanherck2, Arnaud Marchand2, Bruce Carr3, Gene Dubowchik3, Reese Caldwell3, Volkan Granit3, Lawrence Marcin3, David Pirman3, Patrick Chaltin4, Thomas Voets5
1Laboratory of Ion Channel Research, 2CISTIM Leuven vzw, 3Biohaven Pharmaceuticals, Inc, 4CISTIM Leuven vzw and Centre for Drug Design and Discovery (CD3), 5Laboratory of Ion Channel Research and VIB Center for Brain & Disease Research
Objective:
Assess in vitro activity and in vivo efficacy and safety of BHV-2100.
Background:
Transient Receptor Potential Melastatin 3 (TRPM3) is a nonselective cation channel expressed in rodent and human nociceptive neurons. Preclinical models and human genetics implicate TRPM3 in pain signaling. BHV-2100 is a small-molecule TRPM3 antagonist.
Design/Methods:
Activity of BHV-2100 against TRPM3 and selectivity towards other ion channels was evaluated using whole-cell patch-clamp experiments and microfluorimetric calcium measurements in transfected HEK293 cells, rodent dorsal root ganglion neurons, and human stem cell-derived sensory neurons. Implantable sensors monitored the effect of BHV-2100 in rats on body core temperature (BCT) and heart rate (HR). In vivo target engagement was evaluated as the ability of BHV-2100 to inhibit pain responses following intraplantar injection of TRPM3 agonist pregnenolone sulfate (PS) in rodents. Analgesic potential was evaluated in different rodent neuropathic pain models.
Results:
BHV-2100 inhibited human, mouse, and rat TRPM3 with IC50 values between 1-10 nM, showing >1000-fold selectivity over a large panel of other ion channels and receptors. BHV-2100 exhibited high oral bioavailability in rodents, without noticeable lethargy or effects on BCT or HR. BHV-2100 inhibited PS-evoked pain responses in mice and rats with an ED50 of 1.3 mg/kg and 2.5 mg/kg, respectively, and showed dose-dependent efficacy in the sciatic nerve ligation, chemotherapy-induced neuropathic pain, and diabetic neuropathy models.
Conclusions:
BHV-2100 is a potent and selective TRPM3 antagonist that reduces pain in preclinical models without thermoregulatory or sedative effects. These findings support the advancement of BHV-2100 to human trials as a novel potential treatment for pain.