Novel amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids as multifunctional TRPA1 antagonists and PDE4/7 inhibitors: A new approach for the treatment of pain

Chłoń-Rzepa, Grażyna; Ślusarczyk, Marietta; Jankowska, Agnieszka; Gawalska, Alicja; Bucki, Adam; Kołaczkowski, Marcin; Świerczek, Artur; Pociecha, Krzysztof; Wyska, Elżbieta; Zygmunt, Małgorzata; Kazek, Grzegorz; Sałat, Kinga; Pawłowski, Maciej

doi:10.1016/j.ejmech.2018.09.021

Cited by 29 publications

(58 citation statements)

References 61 publications

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“…Our previous studies revealed that both amide and hydrazide 7,8-disubstituted purine-2,6-dione derivatives represent a group of strong and non-selective PDE inhibitors [19][20][21][22]. This and previous experiments allowed us to determine the activity of the studied compounds against PDE1B, 3A, 4B, 4D, and 7A (Table 1).…”

Section: Compounds 832 and 145 But Not 869 Are Prominent Pan-pde Inhmentioning

confidence: 77%

“…Our earlier studies revealed that, compared to selective PDE4 inhibitors (roflumilast or cilomilast), pan-PDE inhibitors might provide better inhibition of the transforming growth factor type β 1 (TGF-β 1 )-induced ASMC remodeling [19]. We have also reported that some of the recently synthesized 7,8-disubstituted purine-2,6-dione derivatives, in addition to being pan-selective PDE inhibitors, can interact with TRPA1 ion channels [20,21]. In this study, we selected three 7,8-disubstituted purine-2,6-dione derivatives ( Figure 1): 832 (a pan-PDE inhibitor), 869 (a TRPA1 modulator), and 145 (a pan-PDE inhibitor and a TRPA1 modulator) and evaluated their ability to limit profibrotic responses of lung fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

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A Novel, Pan-PDE Inhibitor Exerts Anti-Fibrotic Effects in Human Lung Fibroblasts via Inhibition of TGF-β Signaling and Activation of cAMP/PKA Signaling

Wójcik-Pszczoła

Chłoń-Rzepa

Jankowska

et al. 2020

IJMS

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Phosphodiesterase (PDE) inhibitors are currently a widespread and extensively studied group of anti-inflammatory and anti-fibrotic compounds which may find use in the treatment of numerous lung diseases, including asthma and chronic obstructive pulmonary disease. Several PDE inhibitors are currently in clinical development, and some of them, e.g., roflumilast, are already recommended for clinical use. Due to numerous reports indicating that elevated intracellular cAMP levels may contribute to the alleviation of inflammation and airway fibrosis, new and effective PDE inhibitors are constantly being sought. Recently, a group of 7,8-disubstituted purine-2,6-dione derivatives, representing a novel and prominent pan-PDE inhibitors has been synthesized. Some of them were reported to modulate transient receptor potential ankyrin 1 (TRPA1) ion channels as well. In this study, we investigated the effect of selected derivatives (832—a pan-PDE inhibitor, 869—a TRPA1 modulator, and 145—a pan-PDE inhibitor and a weak TRPA1 modulator) on cellular responses related to airway remodeling using MRC-5 human lung fibroblasts. Compound 145 exerted the most considerable effect in limiting fibroblast to myofibroblasts transition (FMT) as well as proliferation, migration, and contraction. The effect of this compound appeared to depend mainly on its strong PDE inhibitory properties, and not on its effects on TRPA1 modulation. The strong anti-remodeling effects of 145 required activation of the cAMP/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway leading to inhibition of transforming growth factor type β1 (TGF-β1) and Smad-dependent signaling in MRC-5 cells. These data suggest that the TGF-β pathway is a major target for PDE inhibitors leading to inhibitory effects on cell responses involved in airway remodeling. These potent, pan-PDE inhibitors from the group of 7,8-disubstituted purine-2,6-dione derivatives, thus represent promising anti-remodeling drug candidates for further research.

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Section: Compounds 832 and 145 But Not 869 Are Prominent Pan-pde Inhmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

A Novel, Pan-PDE Inhibitor Exerts Anti-Fibrotic Effects in Human Lung Fibroblasts via Inhibition of TGF-β Signaling and Activation of cAMP/PKA Signaling

Wójcik-Pszczoła

Chłoń-Rzepa

Jankowska

et al. 2020

IJMS

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“…in neuropathic, oxaliplatin-treated mice. Interestingly, the results of our previous experiments that involved pregabalin as a reference drug indicated that, in mice, cold allodynia could be attenuated only by doses threefold higher than those effectively attenuating tactile allodynia (Chłoń-Rzepa et al, 2018;Furgała, Fijałkowski, et al, 2018;Sałat et al, 2014). This might indicate that cold and tactile allodynia caused by oxaliplatin are mediated by distinct neural mechanisms.…”

Section: Discussionmentioning

confidence: 98%

“…It is however worth noting that, similarly to human studies, in the rodent model we used, duloxetine was only partially effective as an antiallodynic drug and it was not able to fully reverse cold allodynia in neuropathic, oxaliplatin‐treated mice. Interestingly, the results of our previous experiments that involved pregabalin as a reference drug indicated that, in mice, cold allodynia could be attenuated only by doses threefold higher than those effectively attenuating tactile allodynia (Chłoń‐Rzepa et al., ; Furgała, Fijałkowski, et al., ; Sałat et al., ). This might indicate that cold and tactile allodynia caused by oxaliplatin are mediated by distinct neural mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Searching for analgesic drug candidates alleviating oxaliplatin‐induced cold hypersensitivity in mice

2019

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Oxaliplatin is a third‐generation, platinum‐based derivative used to treat advanced colorectal cancer. Within the patient population on oxaliplatin therapy, a lower incidence of hematological adverse effects and gastrointestinal toxicity is noted, but severe neuropathic pain episodes characterized by increased cold and tactile hypersensitivity are present in ~95% of patients. This drug is also used to induce a rodent model of chemotherapy‐induced peripheral neuropathy (CIPN)‐related neuropathic pain which is widely used in the search for novel therapies for CIPN prevention and treatment. This paper provides a step‐by‐step, detailed description of the prevention and intervention protocols used in our laboratory for the assessment of oxaliplatin‐induced cold allodynia in mice. To establish cold sensitivity in mice, the cold plate test was used. Latencies to pain reaction in response to cold stimulus (2.5°C) for vehicle‐treated non‐neuropathic mice, vehicle‐treated mice injected with oxaliplatin (neuropathic control), and oxaliplatin‐treated mice treated additionally with duloxetine are compared. Duloxetine is a serotonin/noradrenaline reuptake inhibitor which was found to produce significant pain relief in patients with CIPN symptoms. In our present study, duloxetine administered intraperitoneally at the dose of 30 mg/kg served as a model antiallodynic drug which attenuated or partially prevented cold allodynia caused by oxaliplatin.

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“…Because of these findings, there is still an interest in identifying new effective PDE4/PDE7 inhibitors mainly as anti-inflammatory agents, although the inhibition of PDE4 could influence ASM tone, and several compounds have been designed and synthesised, such as a series of butanehydrazide derivatives of purine-2,6-dione [30], a series of novel amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-ylalkylcarboxylic acids that inhibit PDE4B/PDE7A activity and also block the human TRPA1 channel, although are more focused on the treatment of pain [31], and some newer substituted 1,3thiazolidine-2,4-dione derivatives [32].…”

Section: Selective Pde Inhibitorsmentioning

confidence: 99%

The future of bronchodilation: looking for new classes of bronchodilators

2019

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@ERSpublicationsThere is a real interest among researchers and the pharmaceutical industry in developing novel bronchodilators. There are several new opportunities; however, they are mostly in a preclinical phase. They could better optimise bronchodilation. http://bit.ly/2lW1q39Cite this article as: Cazzola M, Rogliani P, Matera MG. The future of bronchodilation: looking for new classes of bronchodilators.ABSTRACT Available bronchodilators can satisfy many of the needs of patients suffering from airway disorders, but they often do not relieve symptoms and their long-term use raises safety concerns. Therefore, there is interest in developing new classes that could help to overcome the limits that characterise the existing classes. At least nine potential new classes of bronchodilators have been identified: 1) selective phosphodiesterase inhibitors; 2) bitter-taste receptor agonists; 3) E-prostanoid receptor 4 agonists; 4) Rho kinase inhibitors; 5) calcilytics; 6) agonists of peroxisome proliferator-activated receptor-γ; 7) agonists of relaxin receptor 1; 8) soluble guanylyl cyclase activators; and 9) pepducins. They are under consideration, but they are mostly in a preclinical phase and, consequently, we still do not know which classes will actually be developed for clinical use and whether it will be proven that a possible clinical benefit outweighs the impact of any adverse effect.It is likely that if developed, these new classes may be a useful addition to, rather than a substitution of, the bronchodilator therapy currently used, in order to achieve further optimisation of bronchodilation.

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Novel amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids as multifunctional TRPA1 antagonists and PDE4/7 inhibitors: A new approach for the treatment of pain

Cited by 29 publications

References 61 publications

A Novel, Pan-PDE Inhibitor Exerts Anti-Fibrotic Effects in Human Lung Fibroblasts via Inhibition of TGF-β Signaling and Activation of cAMP/PKA Signaling

A Novel, Pan-PDE Inhibitor Exerts Anti-Fibrotic Effects in Human Lung Fibroblasts via Inhibition of TGF-β Signaling and Activation of cAMP/PKA Signaling

Searching for analgesic drug candidates alleviating oxaliplatin‐induced cold hypersensitivity in mice

The future of bronchodilation: looking for new classes of bronchodilators

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