Research progress and challenges of TRPV1 channel modulators as a prospective therapy for diabetic neuropathic pain

Liu, Chunxia; Miao, Ruoyang; Raza, Fasial; Qian, Hai; Tian, Xin

doi:10.1016/j.ejmech.2022.114893

Cited by 12 publications

(11 citation statements)

References 168 publications

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“…It should also be noted that the 5-alkoxy-1-arylpyrazoles obtained in this work differ in their effect on the TRPV1 ion channel from the antagonists of the group of carboxamide-(I) and urea-substituted (II) pyrazoles (Figure 1). [19,[22][23][24] In addition, the proposed TRPV1 modulators are distinguished by their structural simplicity and, accordingly, high synthetic accessibility from commercially available reagents in one step.…”

Section: Discussionmentioning

confidence: 99%

“…It should also be noted that the 5‐alkoxy‐1‐arylpyrazoles obtained in this work differ in their effect on the TRPV1 ion channel from the antagonists of the group of carboxamide‐ ( I ) and urea‐substituted ( II ) pyrazoles (Figure 1). [19,22–24] …”

Section: Discussionmentioning

confidence: 99%

“…It is estimated that such antagonists may function as potent analgesic agents. [18,19] Comparison of the structures of known TRPV1 modulators [20] allows to predict the general model of their binding site with TRPV1. [21] Their unifying structural feature is the presence of an amide or ureide fragment or their bioisosteres involved in the formation of a hydrogen bond with the active site of the receptor.…”

Section: Introductionmentioning

confidence: 99%

“…One part of the compound contains a lipophilic side chain (apolar part), and on the other side there is a more polar (het)aromatic group (polar part). Among the found chemotypes of TRPV1 modulators, [16] we have highlighted the group of carboxamide-(I) and urea-substituted (II) pyrazoles [19,[22][23][24] (Figure 1) as the most promising for analgesics development, since the pyrazole core is a part of various known analgesics, for example, celecoxib, mavacoxib, metamizole, propyphenazone, aminophenazone and etc. Note that the mechanism of action has not been reliably established for analgesics of the pyrazolone group.…”

Section: Introductionmentioning

confidence: 99%

“…The discovered key function of TRPV1 in pain and inflammatory hyperalgesia have identified a new target for drug development and launched a massive effort on part of the pharmaceutical industry to discover novel TRPV1 antagonists. It is estimated that such antagonists may function as potent analgesic agents [18,19] …”

Section: Introductionmentioning

confidence: 99%

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5‐Alkoxy‐1‐aryl‐3‐polyfluoroalkylpyrazoles with Antinociceptive Activity: Partial Agonists of TRPV1 Ion Channels

et al. 2023

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Chemoselective O‐alkylation of 1‐aryl‐3‐polyfluoroalkylpyrazol‐5‐oles under basic conditions resulted in a series of 5‐alkoxypyrazoles (26 derivatives). They showed an acceptable ADME profile (in silico) and can be considered as drug‐like. In experiments in vivo (CD‐1 mice), it was found that the obtained compounds do not have toxic properties at a dose of more than 150 mg/kg (for most compounds at a dose of >300 mg/kg, and for lead compounds – >600 mg/kg). 22 Compounds from this series demonstrated from moderate to high analgesic effects (28–104 % at 1 h and 37–109 % at 2 h after administration) in vivo in the hot plate test (SD rats, 15 mg/kg, intraperitoneal (ip)). The lead compound was 4‐([1‐phenyl‐3‐(trifluoromethyl)pyrazol‐5‐yl]oxy)butan‐1‐ol, which not only increased the latent period in the hot plate test by 103 % at both measurement points but also showed a pronounced analgesic effect under conditions of capsaicin‐induced nociception (CD‐1 mice, 15 mg/kg, ip). According to molecular modeling, all synthesized compounds can interact with the TRPV1 ion channel. This biological target was confirmed in in vitro experiments on Chinese hamster ovary cells expressing rTRPV1. 5‐Alkoxypyrazoles were partial agonists of the TRPV1 ion channel in various degree, and the most active was the same pyrazole as in in vivo tests.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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5‐Alkoxy‐1‐aryl‐3‐polyfluoroalkylpyrazoles with Antinociceptive Activity: Partial Agonists of TRPV1 Ion Channels

et al. 2023

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ART26.12, a novel fatty acid‐binding protein 5 inhibitor, shows efficacy in multiple preclinical neuropathy models

Warren,

Osborn,

David‐Pereira

et al. 2024

European Journal of Pain

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BackgroundPainful neuropathy is a pathological condition caused by numerous factors including diabetes, chemotherapy or cancer. ART26.12 is a novel fatty acid‐binding protein 5 inhibitor, which our group showed could prevent and treat persistent pain in a preclinical model of oxaliplatin‐induced peripheral neuropathy.MethodsIn the current study, the efficacy of orally dosed ART26.12 was tested in multiple neuropathy models of different aetiology. Paw withdrawal threshold to von Frey monofilaments and latency to escape a cold plate were used as measurements of mechanical and cold sensitivity.ResultsART26.12 (25 and 50 mg/kg BID), dosed prior to the induction of paclitaxel‐induced peripheral neuropathy (PIPN), reversed mechanical allodynia induced by paclitaxel in both male and female rats, and ART26.12 (50 mg/kg BID) prevented the induction of PIPN in female rats. ART26.12 (50 mg/kg BID) also had a protective effect on body weight in the PIPN model. ART26.12 (25 and 100 mg/kg BID) reversed mechanical allodynia when treating established streptozotocin‐induced diabetic neuropathy in male rats. In a model of breast cancer‐induced bone pain in female rats, ART26.12 (100 mg/kg BID) reversed mechanical allodynia within 1 h of dosing. In the same model, ART26.12 (25 mg/kg BID) reversed mechanical allodynia from day 4 of treatment.ConclusionOverall, these preclinical data suggest that ART26.12 is a safe and efficacious therapeutic drug for continued development towards the prevention and treatment of peripheral neuropathy.Significance StatementThis work now shows that ART26.12, a novel and selective inhibitor of FABP5, can prevent and treat multiple preclinical models of peripheral neuropathy. Given its excellent safety profile, further work is warranted to develop ART26.12 as a potential therapeutic tool for pain management.

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Daidzein attenuated paclitaxel-induced neuropathic pain via the down-regulation of TRPV1/P2Y and up-regulation of Nrf2/HO-1 signaling

et al. 2023

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Research progress and challenges of TRPV1 channel modulators as a prospective therapy for diabetic neuropathic pain

Cited by 12 publications

References 168 publications

5‐Alkoxy‐1‐aryl‐3‐polyfluoroalkylpyrazoles with Antinociceptive Activity: Partial Agonists of TRPV1 Ion Channels

5‐Alkoxy‐1‐aryl‐3‐polyfluoroalkylpyrazoles with Antinociceptive Activity: Partial Agonists of TRPV1 Ion Channels

ART26.12, a novel fatty acid‐binding protein 5 inhibitor, shows efficacy in multiple preclinical neuropathy models

Daidzein attenuated paclitaxel-induced neuropathic pain via the down-regulation of TRPV1/P2Y and up-regulation of Nrf2/HO-1 signaling

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