Vanilloid receptor antagonists: emerging class of novel anti-inflammatory agents for pain management

Neuropathic pain affects 26 million patients worldwide resulting in a worldwide healthcare cost over $ 3 billion per year. Despite the availability of an impressive arsenal of powerful drugs for the effective management of pain, there remains a great medical need for new medicines to treat pain. While little is known about the proteins that detect noxious stimuli (especially those of a physical nature), vanilloid receptor, an excitatory ion channel expressed by nociceptors, has been identified as molecular target for the development of recent therapies to treat pain. Initially, the focus was on the development of TRPV1 agonists e.g. capsaicin and resiniferatoxin (RTX) as analgesic agents through the desensitization/denervation approach. While various formulations of capsaicin are either marketed or are currently under development, this approach is often hindered by the pain and discomfort experienced on initial treatment. Thus, TRPV1 antagonists are being evaluated as promising drug candidates to inhibit the transmission of nociceptive signals from the periphery to the CNS and to block other pathological states associated with this receptor. Since the discovery of capsazepine as the first TRPV1 antagonist, multiple classes of antagonists has been reported that can be broadly classified as urea/amide-based and non-urea/non-amide-based agents. However, depending on their chemical structures all these agents can be grouped as benzenesulfonamides, cinnamides, ureas, thio-ureas, amides, benzimidazoles, and piperazine carboxamides, N-aryl-cinnamides etc. The present review will focus on all these antagonists as an emerging class of novel, analgesic, antiinflammatory agents that have been reported in the literature over the last several years and the status of the developmental candidates in various stages of clinical trials.