Safety, Pharmacokinetics, and Pharmacodynamics Study in Healthy Subjects of Oral NEO6860, a Modality Selective Transient Receptor Potential Vanilloid Subtype 1 Antagonist

Brown, W. A.; Leff, Richard L.; Griffin, Andrew M.; Hossack, Stuart; Aubray, Roxane; Walker, Philippe; Chiche, D.

doi:10.1016/j.jpain.2017.01.009

Cited by 45 publications

(38 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All thermally neutral TRPV1 antagonists reported so far seem to fit this scenario. Nilius and Szallasi point at 2 compounds, PHE377 and JTS‐653, as potential exceptions, but do not support their claim with data.…”

Section: Discussionmentioning

confidence: 77%

“…They have no potent effect on the proton activation mode, and they have no effect on deep T b . As all TRPV 1 antagonists, they potently block the capsaicin activation mode, and some of them are also potent blockers of the heat mode (eg capsazepine against rat TRPV 1), whereas others are not (eg NEO 6860 against human TRPV 1). (C) A new functional class of TRPV 1 antagonists was discovered as a by‐product of the search for thermally neutral antagonists.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development

et al. 2018

View full text Add to dashboard Cite

AimThermoregulatory side effects hinder the development of transient receptor potential vanilloid‐1 (TRPV1) antagonists as new painkillers. While many antagonists cause hyperthermia, a well‐studied effect, some cause hypothermia. The mechanisms of this hypothermia are unknown and were studied herein.MethodsTwo hypothermia‐inducing TRPV1 antagonists, the newly synthesized A‐1165901 and the known AMG7905, were used in physiological experiments in rats and mice. Their pharmacological profiles against rat TRPV1 were studied in vitro.ResultsAdministered peripherally, A‐1165901 caused hypothermia in rats by either triggering tail‐skin vasodilation (at thermoneutrality) or inhibiting thermogenesis (in the cold). A‐1165901‐induced hypothermia did not occur in rats with desensitized (by an intraperitoneal dose of the TRPV1 agonist resiniferatoxin) sensory abdominal nerves. The hypothermic responses to A‐1165901 and AMG7905 (administered intragastrically or intraperitoneally) were absent in Trpv1 −/− mice, even though both compounds evoked pronounced hypothermia in Trpv1 +/+ mice. In vitro, both A‐1165901 and AMG7905 potently potentiated TRPV1 activation by protons, while potently blocking channel activation by capsaicin.Conclusion TRPV1 antagonists cause hypothermia by an on‐target action: on TRPV1 channels on abdominal sensory nerves. These channels are tonically activated by protons and drive the reflectory inhibition of thermogenesis and tail‐skin vasoconstriction. Those TRPV1 antagonists that cause hypothermia further inhibit these cold defences, thus decreasing body temperature.SignificanceTRPV1 antagonists (of capsaicin activation) are highly unusual in that they can cause both hyper‐ and hypothermia by modulating the same mechanism. For drug development, this means that both side effects can be dealt with simultaneously, by minimizing these compounds’ interference with TRPV1 activation by protons.

show abstract

Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development

et al. 2018

View full text Add to dashboard Cite

show abstract

“…A study in dogs with hip OA using oral ABT116 did not improve the total pain score, pain severity or pain interference score, but did reduce rescue medication use, increased night time activity levels and briefly produced an acute hyperthermic effect. NEO 6860, which is specific for blocking capsaicin activation of the target, with little or no effect against pH or heat activation, underwent a first-in-human phase I trial of the safety and efficacy of the drug in healthy human subjects [54]. The dose ranging study included 64 subjects and measured pharmacodynamics with a intradermal capsaicin test as well as pharmacokinetics.…”

Section: Arthritis Model Experiments Results Referencementioning

confidence: 99%

The Use of Neurotoxins for Palliative Treatment of Chronic Joint Pain

Krug¹

2019

From Conventional to Innovative Approaches for Pain Treatment

View full text Add to dashboard Cite

Osteoarthritis is a significant public health problem and is rapidly increasing in prevalence with the aging population. Pain is the most disabling consequence of osteoarthritis. Treatment for pain is inadequate and needs to be addressed with new therapeutic modalities. Chronic pain is often the result of peripheral and central pain sensitization which reduces the pain threshold and increases the perceived pain response to noxious and even non-noxious stimuli. Neurotoxins can reduce this sensitization by various mechanisms and are a fertile area of research for the treatment of chronic pain. Botulinum toxins, vanilloids, and conotoxin have all been studied for the treatment of chronic pain. Botulinum toxins and vanilloids have the greatest potential as analgesics for chronic joint pain thus far. Monoclonal antibodies directed against nerve growth factor have also been developed for the treatment of chronic joint pain due to osteoarthritis. These antibodies are not technically neurotoxins but have significant analgesic potential. However, they may have undesirable side effects and are still being evaluated as possible therapies for chronic osteoarthritis pain.

show abstract

“…The vanilloid receptor, TRPV1, is identified as an important detector of pain, including heat hyperalgesia, postherpetic neuralgia, and osteoarthritic pain (Moran, 2018). Small molecule antagonists and agonists targeting TRPV1, such as NEO6860, V116517, and capsaicin, have attracted attention in research on multiple pain pathways and have been shown to have clinical potential for use in sustained pain relief (Szallasi et al, 2006;Arendt-Nielsen et al, 2016;Brown et al, 2017;Blair, 2018). However, safety issues, such as impaired noxious heat sensation and hyperthermia, require special consideration.…”

Section: The Trp Ion Channel Familymentioning

confidence: 99%

“…However, safety issues, such as impaired noxious heat sensation and hyperthermia, require special consideration. Although several recent clinical trials suggested no increase in body temperature in humans (Arendt-Nielsen et al, 2016;Brown et al, 2017), most TRPV1 antagonists examined previously showed on-target adverse effects (Lee et al, 2017;Manitpisitkul et al, 2018), thus limiting their clinical acceptance. The balance between drug efficacy and side effects in clinical trials remains to be explored.…”

Section: The Trp Ion Channel Familymentioning

confidence: 99%

Novel Targets for Stroke Therapy: Special Focus on TRPC Channels and TRPC6

Liu

Chen

et al. 2020

Front. Aging Neurosci.

View full text Add to dashboard Cite

Stroke remains a leading cause of death, disability, and medical care burden worldwide. However, transformation from laboratory findings toward effective pharmacological interventions for clinical stroke has been unsatisfactory. Novel evidence has been gained on the underlying mechanisms and therapeutic potential related to the transient receptor potential (TRP) channels in several disorders. The TRP superfamily consists of a diverse group of Ca 2+ permeable non-selective cation channels. In particular, the members of TRP subfamilies, TRP canonical (TRPC) channels and TRPC6, have been found in different cell types in the whole body and have high levels of expression in the central nervous system (CNS). Notably, the TRPCs and TRPC6 channel have been implicated in neurite outgrowth and neuronal survival during normal development and in a range of CNS pathological conditions. Recent studies have shown that suppression of TRPC6 channel degradation prevents ischemic neuronal cell death in experimental stroke. Accumulating evidence supports the important functions of TRPC6 in brain ischemia. We have highlighted some crucial advancement that points toward an important involvement of TRPCs and TRPC6 in ischemic stroke. This review will make an overview of the TRP and TRPC channels due to their roles as targets for clinical trials and CNS disorders. Besides, the primary goal is to discuss and update the critical role of TRPC6 channels in stroke and provide a promising target for stroke prevention and therapy.

show abstract

Safety, Pharmacokinetics, and Pharmacodynamics Study in Healthy Subjects of Oral NEO6860, a Modality Selective Transient Receptor Potential Vanilloid Subtype 1 Antagonist

Cited by 45 publications

References 13 publications

TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development

TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development

The Use of Neurotoxins for Palliative Treatment of Chronic Joint Pain

Novel Targets for Stroke Therapy: Special Focus on TRPC Channels and TRPC6

Contact Info

Product

Resources

About