Clinical and Preclinical Experience with TRPV1 Antagonists as Potential Analgesic Agents

Gomtsyan, Arthur; Brederson, Jill-Desiree

doi:10.1016/b978-0-12-420024-1.00008-4

Cited by 11 publications

(21 citation statements)

References 63 publications

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“…The therapeutic value of TRPV1 antagonists has been investigated and numerous compounds are now in clinical trial for different pathologies . The TRPV1 antagonist ABT‐102 (Fig.…”

Section: Clinical Trialsmentioning

confidence: 99%

“…The TRPV1 antagonist PHE377 (Fig. , probable chemical structure taken from the patent publication) has completed a phase I clinical trial aimed to treat diabetic pain and postherpetic neuralgia, but the results have not been disclosed and now it has been withdrawn (http://adisinsight.springer.com/).…”

Section: Clinical Trialsmentioning

confidence: 99%

“…DWP‐05195 (Fig. , probable chemical structure taken from the patent publication) is now in Phase II for postherpetic neuralgia treatment as oral administration (http://ClinicalTrials.gov Identifier: NCT01557010). No study results have been disclosed.…”

Section: Clinical Trialsmentioning

confidence: 99%

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Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

Tabrizi

Baraldi

et al. 2016

Medicinal Research Reviews

120

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Transient receptor potential vanilloid 1 (TRPV1) is an ion channel expressed on sensory neurons triggering an influx of cations. TRPV1 receptors function as homotetramers responsive to heat, proinflammatory substances, lipoxygenase products, resiniferatoxin, endocannabinoids, protons, and peptide toxins. Its phosphorylation increases sensitivity to both chemical and thermal stimuli, while desensitization involves a calcium-dependent mechanism resulting in receptor dephosphorylation. TRPV1 functions as a sensor of noxious stimuli and may represent a target to avoid pain and injury. TRPV1 activation has been associated to chronic inflammatory pain and peripheral neuropathy. Its expression is also detected in nonneuronal areas such as bladder, lungs, and cochlea where TRPV1 activation is responsible for pathology development of cystitis, asthma, and hearing loss. This review offers a comprehensive overview about TRPV1 receptor in the pathophysiology of chronic pain, epilepsy, cough, bladder disorders, diabetes, obesity, and hearing loss, highlighting how drug development targeting this channel could have a clinical therapeutic potential. Furthermore, it summarizes the advances of medicinal chemistry research leading to the identification of highly selective TRPV1 antagonists and their analysis of structure-activity relationships (SARs) focusing on new strategies to target this channel.

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“…The therapeutic value of TRPV1 antagonists has been investigated and numerous compounds are now in clinical trial for different pathologies . The TRPV1 antagonist ABT‐102 (Fig.…”

Section: Clinical Trialsmentioning

confidence: 99%

Section: Clinical Trialsmentioning

confidence: 99%

See 1 more Smart Citation

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

Tabrizi

Baraldi

et al. 2016

Medicinal Research Reviews

120

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“…To overcome these drawbacks, a new class of TRPV-1 antagonists with new pharmacological profile was developed. Unlike the old ones, the new class of antagonists either maintained or partly inhibited acid activation of TRPV-1, resulting in a reduced alteration in thermosensation in preclinical tests [5]. No clinical data are available so far for them.…”

mentioning

confidence: 99%

“…Anandamide, a main endogenous cannabinoid endowed also with agonistic effect on TRPV-1,was able to protect gastric mucosa from injury induced by restrain stress in rats and this effect was partially mediated by sensory nerves [4]. Some pharmaceutical companies have discovered and developed potent small-molecule TRPV-1 antagonists (AZD-1386, SB-705498, MK-2295, MR-1817, JTS-653, PHE377, DWP05195, GRC6211) and tested them in Phase I-II clinical trials in search of analgesics for neuropathic, osteoarthritic, dental or esophageal pain [5]. Unfortunately, several candidate molecules showed critical side effects such as hyperthermia and impaired noxious heat sensation in humans and/or did not reach the clinical target.…”

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confidence: 99%

Novel therapeutics in the field of capsaicin and pain

Evangelista

2015

Expert Review of Clinical Pharmacology

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Challenges to develop novel anti‐inflammatory and analgesic drugs

Botz

Bölcskei

Helyes

2016

WIREs Nanomed Nanobiotechnol

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Chronic inflammatory diseases and persistent pain of different origin represent common medical, social, and economic burden, and their pharmacotherapy is still an unresolved issue. Therefore, there is a great and urgent need to develop anti-inflammatory and analgesic agents with novel mechanisms of action, but it is a very challenging task. The main problem is the relatively large translational gap between the preclinical experimental data and the clinical results due to characteristics of the models, difficulties with the investigational techniques particularly for pain, as well as species differences in the mechanisms. We summarize here the current state-of-the-art medication and related ongoing strategies, and the novel targets with lead molecules under clinical development. The first members of the gold-standard categories, such as nonsteroidal anti-inflammatory drugs, glucocorticoids, and opioids, were introduced decades ago, and since then very few drugs with novel mechanisms of action have been successfully taken to the clinics despite considerable development efforts. Several biologics targeting different key molecules have provided breakthrough in some autoimmune/inflammatory diseases, but they are expensive, only parenterally available, their long-term side effects often limit their administration, and they do not effectively reduce pain. Some kinase inhibitors and phosphodiesterase-4 blockers have recently been introduced as new directions. There are in fact some promising novel approaches at different clinical stages of drug development focusing on transient receptor potential vanilloid 1/ankyrin 1 channel antagonism, inhibition of voltage-gated sodium/calcium channels, several enzymes (kinases, semicarbazide-sensitive amine oxidases, and matrix metalloproteinases), cytokines/chemokines, transcription factors, nerve growth factor, and modulation of several G protein-coupled receptors (cannabinoids, purinoceptors, and neuropeptides). WIREs Nanomed Nanobiotechnol 2017, 9:e1427. doi: 10.1002/wnan.1427 For further resources related to this article, please visit the WIREs website.

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Clinical and Preclinical Experience with TRPV1 Antagonists as Potential Analgesic Agents

Cited by 11 publications

References 63 publications

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

Novel therapeutics in the field of capsaicin and pain

Challenges to develop novel anti‐inflammatory and analgesic drugs

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