Target Analysis - Purinoreceptors
P2X3 and P2X7 receptors
Moving away from the circulatory system, and demonstrating the wide expression of P2 purinoreceptors throughout the body, expression of P2X3 receptors is also highly localized on sensory neurones involved in the perception of pain, and the peripheral or spinal application of ATP and other agonists has been shown to induce pain responses and enhance sensitivity to noxious stimuli. The role of P2X3 receptors in pain has been validated, with hypoalgesia being observed in gene knockout and gene silencing studies. The localization of the receptors has made them an attractive target for the development of selective analgesics.
One company with a strong presence in purinoreceptor therapeutics is Evotec, an emerging biotech company with a robust pipeline of drugs primarily for the treatment of CNS disorders and pain. Evotec's P2X3 and P2X2/3 antagonist program is in the lead optimization stage of preclinical development with compounds expected to enter the clinic in 2009. Evotec is predicting that its drugs will achieve first- and best-in-class status, with development of Abbott's P2X2/3 receptor antagonist (A-317491) being dropped. While showing promise in preclinical studies, A-317491 was shelved on account of poor oral bioavailability and serves as an example of how the pharmaceutical industry has faced difficulty in synthesizing clinically-viable drug-like molecules against these two targets.
P2X7 receptors have been the most baffling to researchers but have also attracted much interest from the pharmaceutical industry. The complex signalling and puzzling cellular effects of P2X7 receptor activation have not deterred drug discovery efforts. An important role for P2X7 receptors in the regulation of cytokines has been recognized. This has prompted a number of companies to begin development of P2X7 receptor antagonists for the treatment of inflammatory diseases including RA and inflammatory bowel disease (IBD).
The most advanced P2X7 receptor antagonist is Pfizer's CE- 224535, which is currently in the Phase IIa portion of a Phase II/III trial in RA patients who are inadequately controlled with methotrexate, the current standard treatment. It is yet to be seen what role, if any, P2X7 receptor antagonists will have in the treatment of RA. P2X7 receptor antagonists have been tested for a number of indications, many of which have been discontinued; for example, a Phase II trial of the anti-inflammatory and analgesic efficacy of CE-224535 in osteoarthritis knee pain was terminated after an interim analysis showed a lack of efficacy compared to placebo. Another advanced P2X7 receptor antagonist is AstraZeneca's AZD-9056, which is in Phase II trials for RA. Like CE-224535, its potential for osteoarthritis was investigated but subsequently discontinued. Additionally, development programmes for IBD and chronic obstructive pulmonary disease (COPD) were also terminated. AZD-9056 is currently under development for RA with submissions for approval expected in 2012. Returning to Evotec, the company has launched a Phase I study for its P2X7 antagonist. The trial will examine the pharmacokinetics, safety and tolerability of the compound following oral administration in healthy volunteers.
Recently, genetic variations in the P2X7 receptor gene have been studied in populations suffering from major depressive disorder (MDD) and bipolar affective disorders. One variation has been demonstrated to be strongly associated with both MDD and bipolar affective disorders. This has provided an impetus to develop drugs for the P2X7 receptor to target depression. Affectis Pharmaceuticals, a German biopharmaceutical company, is investigating potential drugs for the treatment of depression and schizophrenia. AF-4025, its P2X7 receptor agonist for the treatment of depression has completed preclinical testing and is planned for clinical development. The company also has P2X7 receptor antagonists in the late stages of lead optimization.
