Discovery of (S)–N-(3-isopropylphenyl)-2-(5-phenylthiazol-2-yl)pyrrolidine-1-carboxamide as potent and brain-penetrant TRPV1 antagonist

Qiao, Yunfei; Qiao, Zhenrui; He, Wei; Chen, Yingda; Song, Depu; Wang, Guohao; Guo, Ning; Shao, Lulian; Tian, Zhiyong; Wang, Qiang; Yang, Lin; Qian, Hai

doi:10.1016/j.ejmech.2022.114191

Cited by 13 publications

(5 citation statements)

References 31 publications

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“…Based on the in vitro antagonistic activity of the compounds, four compounds with potent antagonistic activity were selected for further in vivo analgesic evaluation. We use three classic animal pain models to test the analgesic effects of the preferred compounds (Qiao et al., 2022; Wang et al., 2018; Wang, Han, Yang, Chen, et al., 2020; Wang, Han, Yang, Zhou, et al., 2020; Yang et al., 2014). In case of the acetic acid‐induced twisting experiment (Figure 2a), a 0.6% acetic acid solution was injected intraperitoneally to observe and record the number of twisting reactions (abdominal concavity, extension of hind limbs, and hip elevation) that occurred in mice within 15 min.…”

Section: Resultsmentioning

confidence: 99%

Novel phenylpiperazine derivatives as potent transient receptor potential vanilloid 1 antagonists

Jing,

Liu

2024

Chem Biol Drug Des

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Transient receptor potential vanilloid 1 (TRPV1) is a non‐selective cation channel, which is considered a highly validated target for pain perception. Repeated activation with agonists to desensitize receptors or use the antagonists can both exert analgesic effects. In this work, two series of novel phenylpiperazine derivatives were designed, synthesized, and evaluated for the in vitro receptor inhibitory activity and in vivo analgesic activity. Among them, L‐21 containing sulfonylurea group was identified with potent TRPV1 antagonistic activity and analgesic activity in various pain models. At the same time, L‐21 exhibited low risk of hyperthermia side effect. These results indicated that L‐21 is a promising candidate for further development of novel TRPV1 antagonist to treat pain.

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Section: Resultsmentioning

confidence: 99%

Novel phenylpiperazine derivatives as potent transient receptor potential vanilloid 1 antagonists

Jing,

Liu

2024

Chem Biol Drug Des

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“…The next generation of TRPV1 antagonists with greater target selectivity and better penetration into the central nervous system is being designed and tested. One such compound, MDR-652, has shown promise as a potential TRPV1 antagonist, with improved selectivity and penetration into the central nervous system ( Qiao et al, 2022 ).…”

Section: Clinical Applicationmentioning

confidence: 99%

Ion channels in cancer-induced bone pain: from molecular mechanisms to clinical applications

Lu,

Wu,

Wei

2023

Front. Mol. Neurosci.

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Cancer-induced bone pain (CIBP) caused by bone metastasis is one of the most prevalent diseases, and current treatments rely primarily on opioids, which have significant side effects. However, recent developments in pharmaceutical science have identified several new mechanisms for CIBP, including the targeted modification of certain ion channels and receptors. Ion channels are transmembrane proteins, which are situated on biological cell membranes, which facilitate passive transport of inorganic ions across membranes. They are involved in various physiological processes, including transmission of pain signals in the nervous system. In recent years, there has been an increasing interest in the role of ion channels in chronic pain, including CIBP. Therefore, in this review, we summarize the current literature on ion channels, related receptors, and drugs and explore the mechanism of CIBP. Targeting ion channels and regulating their activity might be key to treating pain associated with bone cancer and offer new treatment avenues.

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“…Recent findings have however discovered (S)-N-(3-isopropylphenyl)-2-(5phenylthiazol-2-yl) pyrrolidine-1-carboxamide to be a powerful and brain-penetrant TRPV1 antagonist. 51,52 Animal model studies employing TRPV1 antagonist, GRC-6211 suggested therapeutic potency in suppressing chronically inflamed bladder hyperactivity, although clinical studies pertaining to their implication in human subjects remain to be established. Antagonist like MK-2295 was withdrawn owing to the burn injuries and AMG-517 due to febrile reactions.…”

Section: Trpv1 As a Drug Targetmentioning

confidence: 99%

“…Recent findings have however discovered (S)–N-(3-isopropylphenyl)-2-(5-phenylthiazol-2-yl) pyrrolidine-1-carboxamide to be a powerful and brain-penetrant TRPV1 antagonist. 51 , 52 …”

Section: Trpv1 As a Drug Targetmentioning

confidence: 99%

A Comprehensive Review on the Regulatory Action of TRP Channels: A Potential Therapeutic Target for Nociceptive Pain

Anand,

Rajagopal

2023

J Exp Neurosci

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The transient receptor potential (TRP) superfamily of ion channels in humans comprises voltage-gated, non-selective cation channels expressed both in excitable as well as non-excitable cells. Four TRP channel subunits associate to create functional homo- or heterotetramers that allow the influx of calcium, sodium, and/or potassium. These channels are highly abundant in the brain and kidney and are important mediators of diverse biological functions including thermosensation, vascular tone, flow sensing in the kidney and irritant stimuli sensing. Inherited or acquired dysfunction of TRP channels influences cellular functions and signaling pathways resulting in multifaceted disorders affecting skeletal, renal, cardiovascular, and nervous systems. Studies have demonstrated the involvement of these channels in the generation and transduction of pain. Based on the multifaceted role orchestrated by these TRP channels, modulation of the activity of these channels presents an important strategy to influence cellular function by regulating intracellular calcium levels as well as membrane excitability. Therefore, there has been a remarkable pharmaceutical inclination toward TRP channels as therapeutic interventions. Several candidate drugs influencing the activity of these channels are already in the clinical trials pipeline. The present review encompasses the current understanding of TRP channels and TRP modulators in pain and pain management.

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Discovery of (S)–N-(3-isopropylphenyl)-2-(5-phenylthiazol-2-yl)pyrrolidine-1-carboxamide as potent and brain-penetrant TRPV1 antagonist

Cited by 13 publications

References 31 publications

Novel phenylpiperazine derivatives as potent transient receptor potential vanilloid 1 antagonists

Novel phenylpiperazine derivatives as potent transient receptor potential vanilloid 1 antagonists

Ion channels in cancer-induced bone pain: from molecular mechanisms to clinical applications

A Comprehensive Review on the Regulatory Action of TRP Channels: A Potential Therapeutic Target for Nociceptive Pain

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