JTC-801 an orally active ORL1 antagonist for the treatment of neuropathic pain

It has been estimated that 9% of the US population suffers from moderate to severe non-cancer-related pain. Acute pain resulting from conditions such as headache, muscle spasms, dental problems or following surgery, affects 90 million Americans every year. Chronic pain is more troubling as it sparks a viscous cycle of clinical problems and often precipitates depression and/or life-style changes. Furthermore, establishing prolonged analgesia, free of serious side effects is a particularly challenging area of medicine. Estimates of the number of Americans suffering chronic pain range from 40-70 million. The total economic cost of pain is $100 (US) billion in the US alone and the estimated worldwide market for pain and inflammation treatments has been estimated as $18.7 (US) billion. It is therefore not surprising that the development of analgesics has represented a major pharmaceutical objective. .

Nociceptin is an endogenous ligand for the opioid receptor-like1 (ORL1) G-protein coupled receptor. This ligand and its receptor are localized in various regions of the central nervous system, which are associated with nociception. The pain modulation of nociceptin has been shown in various rat pain models. However, most reports regarding nociceptin pain modulation used intrathecal or intracerebroventricular administration, while only a few have utilized systemic nociceptin. In their recent Neuroscience Letters paper, Suyama et al investigate the anti-nociceptive effects of systemic JTC-801, a recently synthesized novel and oral active ORL1 receptor antagonist. It has been demonstrated that JTC-801 antagonizes ORL1 receptor responses, and also has efficacious and potent antinociceptive effects in acute pain animal models, not only by intravenous injection but also oral administration. In the present study, the efficacy of JTC-801 in a model of neuropathic pain, chronic constriction injury of the sciatic nerve was investigated.

This study demonstrates that oral JTC-801 significantly reduces heat allodynia over an extended period of time. Neuropathic pain is associated with a variety of etiologies including trauma, infection, diabetes, immune deficiencies, ischemic disorders, and toxic neuropathies. Approximately 26 million patients are affected worldwide and the lifestyle of this cohort can be severely impeded, a problem compounded by the lack of efficacy and frequent incidence of side effects associated with current treatment options. The efficacy of JTC-801 may therefore offer hope for the future treatment of a largely unmet condition.

Over 10 million Americans suffer from osteoporosis and a further 32.9 million have low bone mass, placing them at an increased risk for developing this condition. Patients with these conditions carry an increased risk of sustaining fractures, which are both clinically problematic and costly to healthcare systems, and the development of new osteoporosis treatments therefore offers immense opportunities to the pharmaceutical industry. The global osteoporosis therapies market, including estrogen replacement therapy drugs was estimated at $5.5 billion in 2001 and projected to double by 2008 in the face of population aging, decreased bone quality and increased awareness of osteoporosis (for a full analysis of osteoporosis therapeutics click here). Although the vast majority of cases of osteoporosis are primary and are hormonal in nature, secondary osteoporosis accounts for <5% of osteoporosis cases. Causes include endocrine disease and steroid usage. Suyama et al have demonstrated that osteoporosis occurs following chronic constriction injury of the sciatic nerve. In their recent study, Suyama et al have not only demonstrated that oral JTC-801 reduces heat allodynia but that it also reduces associated osteoporosis.

Entry date Thursday, January 22, 2004

Adapted from Suyama et al, Neurosci Lett. 2003 Nov 20; 351(3): 133-6.