The worldwide analgesic market was worth $38 billion during the year 2002 and is expected to nearly double to $75 billion by the year 2010 (for a recent and in depth insight see Pain Therapeutics - Drugs, Markets and Companies). The vanilloid receptor TRPV1 (VR1) has now become an attractive molecular target for multiple sub-types of pain. Abbott researchers have recently described the development of A-425619, a low nanomolar TRPV1 antagonist. This molecule blocks heat hypersensitivity in a model of inflammatory pain as well as posoperative and arthritic algesia. Although A-425619 was demonstrated to have considerable potential as an anti-hyperalgesic agent and effect on neuropathic pain was not observed.

The worldwide analgesic market was worth $38 billion during the year 2002 and is expected to nearly double to $75 billion by the year 2010 (for a recent and in depth insight see Pain Therapeutics - Drugs, Markets and Companies).

The vanilloid, capsaicin has long been known to stimulate pain pathways through the release of a variety of sensory afferent neurotransmitters. In 1997 Caterina et al cloned the first vanilloid receptor (VR1 now known as TRPV1) and showed that it is a receptor-coupled non-selective cation channel permeable to calcium and responsive to noxious stimuli. TRPV1 receptors were later found to be present in spinal cord and caudal brainstem, medullary structures important for mediating sensory signals from the viscera and also in afferent fibers emanating from the bladder. TRPV1 has now become an attractive molecular target for various indications including multiple sub-types of pain.

Numerous pain etiologies have been described including inflammatory pain where various inflammatory mediators sensitize afferent pathways. An interesting property of TRPV1 is that inflammatory mediators are able to modulate its activity and bradykinin, NGF and ATP have each been shown to sensitize TRPV1. This suggests that such interactions play key roles in the integration of noxious signals after inflammation or tissue injury.

Vanilloid agonists and antagonists are both currently being developed for the treatment of pain; agonists work through desensitizing the receptor while antagonists block its stimulation by (patho)physiological ligands. Capsezapine was the first TRPV1 antagonist to be developed however low activity and poor selectivity has restricted its use to an experimental tool used to investigate vanilloid (patho)physiology. Newer antagonists such as BCTC, SB-366791, AMG9810, and 5-iodo-resiniferatoxin have all been developed and in the highlighted JPET study and its companion paper, Abbott researchers describe the development of a further antagonist, A-425619.

A-425619, discovered through HTS, was shown to antagonize capsaicin stimulation of human recombinant TRPV1 with an IC50 of 5nM (compared to 149 nM for capsazepine). When screened against a broad panel of other receptors, enzymes and ion transporters, A-425619 was found to be highly selective for TRPV1 receptors. In addition to being active at human TRPV1, A-425619 also potently antagonized the rat TRPV1 receptor thus allowing (patho)physiological characterization in this species. Of importance to the potential role of A-425619 as a candidate for the treatment of inflammatory pain, antagonist activity was evaluated under conditions where TRPV1 had been sensitized. Although the authors of the JPET study did not use inflammatory mediators to sensitize the receptor, they did find that A-425619 remained active as an inhibitor of TRPV1 when the channel was stimulated by capsaicin, heat, or acidic conditions in the presence of a PKC activator. PKC has been shown to be a down-stream mediator of TRPV1 sensitization.

A-425619 was further characterized by Honore et al in an accompanying paper. A-425619 was found to have moderate bioavailabilty when dosed orally (46%) and better bioavailability (83%) when administered ip. Plasma elimination half-life was 0.6 hours when given iv. Oral administration of A-425619 prevented capsaicin-induced mechanical hyperalgesia (capsaicin was administered locally to the paw) with an ED50 of 45 μmol/kg; full efficacy was observed at 100 μml/kg.

Having demonstrated efficacy against non-sensitized TRPV1 receptors, the authors investiagted the efficacy of A-425619 in an inflammatory state (induced by Freund's adjuvant). A-425619 was found to block heat hypersensitivity, with an efficacy of approximately 50 μmol/kg po. When administered ip, the effect was rapid (within 15 minutes) and long-lasting (longer than 8 hours); it should be noted that time course data was not reported for oral administration. Of importance A-425619 had no effect on heat hypersensitivity in contralateral non-inflamed paws, indicative of a specific antihyperalgesic effect in this model. This is important since it suggests that A-425619 would not affect normal defensive to heat. In addition to not affecting non-pathological pain responses, A-425619 also failed to alter motor coordination or spontaneous exploratory activity suggesting a lack of CNS-related adverse effects. These data suggest that A-425619 represents a potential candidate for the treatment of inflammatory pain.

Pain has multiple etiologies and in addition inflammatory pain, postoperative pain represents a major market (see Postoperative Pain: Dynastat Cutting Up The Pain Market). Postoperative pain affects up to 53m patients in the US alone. Despite most patients receiving some form of pain management, over half of these patients still experience inadequate pain relief. Morphine, one of the most commonly used post-surgical analgesics although it has significant adverse effects and is characterized by diminished efficacy over time. The Abbott researchers therefore investigated the potential of A-425619 to treat postoperative pain. They found that A-425619 reduced skin incision-induced thermal and mechanical hyperalgesia although efficacy was greater (especially for mechanical hyperalgesia) when administered one day post-surgery. Of interest, and in contrast to morphine, the efficacy of A-425619 was maintained over a chronic dosing schedule. This interesting data suggests that A-425619 may be of particular use as the analgesic benefits of morphine start to decline. Osteoarthritis also represents a major pain market and A-425619 was found to be active in a model of this pain state.

These studies therefore demonstrate that A-425619 has considerable potential as an anti-hyperalgesic agent. Indications could include inflammatory, arthritic and postoperative pain. Disappointingly however these studies failed to demonstrate a major effect in models of neuropathic pain, one of the most difficult areas of pain to treat. This lack of effect contrast with an impressive reduction by BCTC in mechanical hyperalgesia in a sciatic nerve injury model (Pomonis et al, 2003) and may be due to low CNS penetrability by A-425619.

Entry date Wednesday, June 01, 2005

J Pharmacol Exp Ther. 2005 Apr 18; [Epub ahead of print]