Clinical development of TRPV1 antagonists: targeting a pivotal point in the pain pathway

TRPV1 is a noxious heat, capsaicin (vanilloid) and acid receptor for which the development of antagonists represents a novel therapeutic approach for the treatment of pain. TRPV1 antagonists have entered early clinical development and initial reports indicate that they have demonstrated pharmacodynamic effects consistent with TRPV1 antagonist activity and anti-hyperalgesic action in humans. Should these effects extend to the relief of symptoms experienced by patients with chronic pain then this class of compounds may offer one of the first novel mechanisms of action for the treatment for pain for many years. In this article we will discuss recent progress and challenges in the field in this highly competitive area of drug discovery.

Introduction

The unmistakable pungency of capsaicin, a component of chilli peppers, and other natural products that act at the ‘vanilloid receptor’ has led to much basic research into TRPV1 function and an appreciation that this ion channel acts as a key signalling complex in the pain pathway [1]. TRPV1 is primarily found on small diameter primary afferents, particularly unmyelinated C-fibres and thinly myelinated A-δ fibres but is also expressed, albeit at apparently lower levels, in upstream parts of the pain pathway such as the spinal cord and brain 2, 3, 4. Besides being activated by capsaicin (Fig. 1), TRPV1 also responds to a wide range of exogenous and endogenous chemical ligands (e.g. ‘endovanilloids’ such as anandamide) as well as changes in more diverse activators such as protons (acid, pH < 6) and physical stimuli such as heat (>42°C) 5, 6, 7. TRPV1 is also subject to regulation by changes in membrane potential and this intrinsic voltage-dependence is thought to underlie the gating mechanism of this non-selective cation channel [8] which leads to the influx of Na⁺ and Ca²⁺ ions into cells. Importantly, TRPV1 activity is also subject to regulation by a host of intracellular signalling cascades that are implicated in the response to algogenic agents, inflammatory mediators and injury (Fig. 2). Overall, this points towards a role of TRPV1 as a key integrator of a diverse array of activators and downstream regulatory pathways that can act in concert to recruit or enhance TRPV1 activity in parts of the peripheral and central nervous system resulting in ongoing or ‘inappropriate’ neuronal activity that may ultimately be perceived as chronic pain.

Characterisation of TRPV1 knockout (KO) mice, which were engineered to lack both copies of the TRPV1 gene, provided pivotal evidence for the key role of TRPV1 in pain. Although phenotypically normal, and virtually inseparable from their littermates in terms of behaviour, these animals show a clear attenuation of the thermal hyperalgesia associated with inflammation 9, 10. These findings provided a strong rationale for the development of selective TRPV1 antagonists as a novel pain therapy with the potential for an improved side effect profile compared to current agents 11, 12. In the period of extensive research that has followed, many novel selective and chemically diverse TRPV1 antagonists have been identified and assessed in preclinical models of pain. For example, BCTC, AMG9810, A425619 and SB-705498 all show good activity in the Freund's complete adjuvant (FCA) model of inflammatory pain 13, 14, 15, 16. Such agents appear to be able to reduce thermal and mechanical hyperalgesia as well as tactile allodynia. Furthermore, TRPV1 antagonists also show efficacy in models of neuropathic pain [15], postoperative pain, cancer pain [17] and the mono-iodoacetate model of osteoarthritis [18]. These data therefore extend the findings of the TRPV1 KO studies and provide a robust pre-clinical rationale for exploring the potential of TRPV1 antagonists for the treatment of a broad range of acute and chronic pain conditions in humans. It is noteworthy that there is also renewed excitement regarding the development of TRPV1 agonist therapies for which recent clinical data have defined the efficacy of injectable and dermal (topical) patch formulations of relatively high concentrations of capsaicin in the treatment of osteoarthritic pain of the knee and in HIV-induced neuropathy. Such approaches capitalise on the desensitising properties of capsaicin but are limited to topical application owing to the issues of systemic side effects associated with capsaicin administration (Table 1). The progress in this field has been reviewed extensively elsewhere [19].

In this article, we will discuss recent progress defining the therapeutic potential of small molecule TRPV1 antagonists as novel analgesic agents and review the current clinical candidates and emerging clinical data for this highly competitive area of drug discovery. The broad therapeutic potential of TRPV1 antagonists for a range of additional indications has been reviewed recently 20, 21, 22 and alternative biological strategies such as the use of antibodies or RNA inhibition to reduce TRPV1 function are also now showing promise (Table 1), but will not be discussed further here.