Novel butanehydrazide derivatives of purine-2,6-dione as dual PDE4/7 inhibitors with potential anti-inflammatory activity: Design, synthesis and biological evaluation

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

doi:10.1016/j.ejmech.2018.01.068

Cited by 40 publications

(43 citation statements)

References 45 publications

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“…The graph shows that both PTX and (±)-LSF significantly and with similar potency reduced levels of TNF-α, while GRMS-55 did not exhibit activity in this test compared to the LPS-treated control. Rolipram, a potent PDE4 inhibitor, a data already published (9,16) at a concentration of 50 μM completely reduced the levels of TNF-α in LPS-stimulated rat blood compared to the control group. Moreover, the activity of this compound was significantly higher than those of PTX and (±)-LSF.…”

Section: Tnf-α Inhibition In Vitromentioning

confidence: 84%

“…The aim of this study was to compare the pharmacological activity of two PDE inhibitors, namely a new 1,3-dimethylpurine-2,6-dione derivative: 4-(1,3-Dimethyl-2,6-dioxo-8-(phenethylamino)-2,3,6,7-tetrahydro-1H-purin-7-yl)-N′-(2-hydroxybenzylidene)butanehydrazide (GRMS-55) and racemic lisofylline ((±)-LSF) to address the issues raised above. GRMS-55 has been chosen from the library of newly designed and synthesized compounds as a moderate inhibitor of PDE4B and a strong inhibitor of PDE7A (16). (±)-LSF is a drug candidate with a moderate PDE4B inhibitory activity tested earlier in pre-clinical and clinical studies as a potential drug for the treatment of inflammatory and autoimmune disorders (9,17).…”

Section: Introductionmentioning

confidence: 99%

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Comparative Assessment of the New PDE7 Inhibitor – GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach

et al. 2020

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Purpose This study aimed to assess the activity of two phosphodiesterase (PDE) inhibitors, namely GRMS-55 and racemic lisofylline ((±)-LSF)) in vitro and in animal models of immune-mediated disorders. Methods Inhibition of human recombinant (hr)PDEs and TNF-alpha release from LPS-stimulated whole rat blood by the studied compounds were assessed in vitro. LPS-induced endotoxemia, concanavalin A (ConA)-induced hepatitis, and collagen-induced arthritis (CIA) animal models were used for in vivo evaluation. The potency of the investigated compounds was evaluated using PK/PD and PK/PD/disease progression modeling. Results GRMS-55 is a potent hrPDE7A and hrPDE1B inhibitor, while (±)-LSF most strongly inhibits hrPDE3A and hrPDE4B. GRMS-55 decreased TNF-alpha levels in vivo and CIA progression with IC 50 of 1.06 and 0.26 mg/L, while (±)-LSF with IC 50 of 5.80 and 1.06 mg/L, respectively. Moreover, GRMS-55 significantly ameliorated symptoms of ConA-induced hepatitis. Conclusions PDE4B but not PDE4D inhibition appears to be mainly engaged in anti-inflammatory activity of the studied compounds. GRMS-55 and (±)-LSF seem to be promising candidates for future studies on the treatment of immunerelated diseases. The developed PK/PD models may be used to assess the anti-inflammatory and anti-arthritic potency of new compounds for the treatment of rheumatoid arthritis and other inflammatory disorders.

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Section: Tnf-α Inhibition In Vitromentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Comparative Assessment of the New PDE7 Inhibitor – GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach

et al. 2020

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“…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%

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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“…Castaño et al [53] showed that PDE7 inhibitors and dual PDE4/7 inhibitors reduced T cell viability (murine T-cell line D10.G4.1). Therefore, one of the therapeutic strategies involves dual PDE4/7 inhibitors, and compounds expressing this double activity are still being sought for the treatment of immune-related disorders [78,79].…”

Section: The Effect Of Dual Pde4/7 Inhibitors On T Cell Activitymentioning

confidence: 99%

Role of Phosphodiesterase 7 (PDE7) in T Cell Activity. Effects of Selective PDE7 Inhibitors and Dual PDE4/7 Inhibitors on T Cell Functions

Szczypka

2020

IJMS

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Phosphodiesterase 7 (PDE7), a cAMP-specific PDE family, insensitive to rolipram, is present in many immune cells, including T lymphocytes. Two genes of PDE7 have been identified: PDE7A and PDE7B with three or four splice variants, respectively. Both PDE7A and PDE7B are expressed in T cells, and the predominant splice variant in these cells is PDE7A1. PDE7 is one of several PDE families that terminates biological functions of cAMP—a major regulating intracellular factor. However, the precise role of PDE7 in T cell activation and function is still ambiguous. Some authors reported its crucial role in T cell activation, while according to other studies PDE7 activity was not pivotal to T cells. Several studies showed that inhibition of PDE7 by its selective or dual PDE4/7 inhibitors suppresses T cell activity, and consequently T-mediated immune response. Taken together, it seems quite likely that simultaneous inhibition of PDE4 and PDE7 by dual PDE4/7 inhibitors or a combination of selective PDE4 and PDE7 remains the most interesting therapeutic target for the treatment of some immune-related disorders, such as autoimmune diseases, or selected respiratory diseases. An interesting direction of future studies could also be using a combination of selective PDE7 and PDE3 inhibitors.

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Novel butanehydrazide derivatives of purine-2,6-dione as dual PDE4/7 inhibitors with potential anti-inflammatory activity: Design, synthesis and biological evaluation

Cited by 40 publications

References 45 publications

Comparative Assessment of the New PDE7 Inhibitor – GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach

Comparative Assessment of the New PDE7 Inhibitor – GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach

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

Role of Phosphodiesterase 7 (PDE7) in T Cell Activity. Effects of Selective PDE7 Inhibitors and Dual PDE4/7 Inhibitors on T Cell Functions

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