IPNP2015 bind to and functionally inhibit in vitro all 3 monoamine transporters (the 5-HT transporter “SERT”, the NA transporter “NAT” and the DA transporter “DAT”) in rodent brain. This data is in agreement with binding results obtained using stable human cell lines expressing these neurotransmitter transporter systems.
Chronic neuropathic pain is a highly devastating condition and affects millions of patients worldwide. It is a multifactorial disease that is treated mainly with selected anticonvulsant or antidepressant drugs. Currently, almost 50% of the patients do not respond to pharmacotherapy. Lack of efficacy as well as safety concerns remain areas of high unmet need and provide a window of opportunity for developing novel treatments. Such treatments should cover mechanisms that prevail regardless of disease etiology. It is thought that various antidepressants can restore the imbalance in monoaminergic control pathways to ameliorate neuropathic hypersensitivity.
IPNP2015 enhance the activity of 5-HT, NA and DA neurotransmission within central pain circuits. This might provide a broader spectrum of pain relief than dual mechanism of action MRIs such as duloxetine. This mechanistic approach represents an exciting opportunity in potentially translating to novel therapeutics for the treatment of chronic pain in humans.
IPNP2015 is active in the mouse FST (forced swim test), a model predictive for antidepressant-like activity in the clinic following acute drug administration. In agreement with both in vitro and in vivo measures of the ability to inhibit DA transporter function, IPNP2015 induced slow-on/slow-off increases in locomotor activity when tested in mice habituated to the test environment. IPNP2015 worked well in rat models of persistent and neuropathic pain. The compound was found to be relatively stable in a multi-species liver microsome screen and has to date shown comparatively few off-target affinities or unwanted effects. Comparative studies revealed that IPNP2015 possesses superior efficacy in these pain models compared with the dual MRI duloxetine. As such it represents an attractive new drug candidate for the treatment of chronic pain.