Identification <i>in Silico</i> and Experimental Validation of Novel Phosphodiesterase 7 Inhibitors with Efficacy in Experimental Autoimmune Encephalomyelitis Mice

Redondo, Miriam; Palomo, Valle; Brea, José; Pérez, Daniel I.; Martín-Álvarez, Rocío; Pérez, Concepción; Paul-Fernández, Nuria; Conde, Santiago; Cadavid, Marı́a Isabel; Loza, Marı́a Isabel; Mengod, Guadalupe; Martı́nez, Ana; Gil, Carmen; Campillo, Nuria E.

doi:10.1021/cn300105c

Cited by 24 publications

(22 citation statements)

References 58 publications

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“…In the present work, we show that allosteric modulation of both PDE7 and GSK-3, using 5-imino-1,2,4-thiadiazoles: (i) reduces symptoms in the EAE animal model of demyelination (as previously reported36) and, (ii) enhances remyelination in two other demyelinating mouse models where demyelination occurs with minimal adaptive immune system contribution (using lysophosphatidylcholine-LPC- or cuprizone). Our results lead us to propose these dual PDE7-GSK3 inhibitors, especially VP3.15 with its good oral bioavailability and CNS penetration, as potential combined anti-inflammatory and pro-remyelinating therapies for MS.…”

supporting

confidence: 85%

“…apremilast. The PDE7-GSK3 inhibitors used here (VP3.15 and VP1.15) have previously also shown an immunomodulatory effect in spinal cord injury models (as well as EAE)3436, without emetic side effects3640.…”

Section: Discussionmentioning

confidence: 89%

“…However, the dual PDE7-GSK3 inhibitor VP3.15 was designed and synthesized as a drug-like molecule with a better safety profile, and improved pharmacodynamic and pharmacokinetic properties3643 (Tables 1 and 2). It shows oral bioavailability and brain penetration in mice after oral and i.p.…”

Section: Resultsmentioning

confidence: 99%

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Promoting in vivo remyelination with small molecules: a neuroreparative pharmacological treatment for Multiple Sclerosis

Medina‐Rodriguez

Bribián

Boyd

et al. 2017

Sci Rep

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Multiple Sclerosis (MS) is a neurodegenerative disease where immune-driven demyelination occurs with inefficient remyelination, but therapies are limited, especially those to enhance repair. Here, we show that the dual phosphodiesterase (PDE)7- glycogen synthase kinase (GSK)3 inhibitor, VP3.15, a heterocyclic small molecule with good pharmacokinetic properties and safety profile, improves in vivo remyelination in mouse and increases both adult mouse and adult human oligodendrocyte progenitor cell (OPC) differentiation, in addition to its immune regulatory action. The dual inhibition is synergistic, as increasing intracellular levels of cAMP by cyclic nucleotide PDE inhibition both suppresses the immune response and increases remyelination, and in addition, inhibition of GSK3 limits experimental autoimmune encephalomyelitis in mice. This combination of an advantageous effect on the immune response and an enhancement of repair, plus demonstration of its activity on adult human OPCs, leads us to propose dual PDE7-GSK3 inhibition, and specifically VP3.15, as a neuroprotective and neuroreparative disease-modifying treatment for MS.

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supporting

confidence: 85%

Section: Discussionmentioning

confidence: 89%

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Promoting in vivo remyelination with small molecules: a neuroreparative pharmacological treatment for Multiple Sclerosis

Medina‐Rodriguez

Bribián

Boyd

et al. 2017

Sci Rep

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“…Moreover, recent studies showed that PDE7 inhibitors could play an anti‐inflammatory and neuroprotective role in cellular and animal models of Parkinson's disease (Morales‐Garcia et al ., ), spinal cord injury (Paterniti et al ., ), Alzheimer's disease (Perez‐Gonzalez et al ., ) and stroke (Redondo et al ., ). In addition, different chemically diverse PDE7 inhibitors have shown efficacy in the EAE model of MS (Redondo et al ., 2012a,b) without inducing emesis (Garcia et al ., ) pointing to a new era of innovative drugs. In this regard, the therapeutical potential for MS treatment of the thioxoquinazoline derivative TC3.6 synthesized in our laboratory has been recently reported.…”

Section: Introductionmentioning

confidence: 99%

PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis

Mestre

Redondo

Carrillo‐Salinas

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSEcAMP plays an important role in the transduction of signalling pathways involved in neuroprotection and immune regulation. Control of the levels of this nucleotide by inhibition of cAMP-specific PDEs such as PDE7 may affect the pathological processes of neuroinflammatory diseases like multiple sclerosis (MS). In the present study, we evaluated the therapeutic potential of the selective PDE7 inhibitor, TC3.6, in a model of primary progressive multiple sclerosis (PPMS), a rare and severe variant of MS. EXPERIMENTAL APPROACHTheiler's murine encephalomyelitis virus-induced demyelinated disease (TMEV-IDD) is one of the models used to validate the therapeutic efficacy of new drugs in MS. As recent studies have analysed the effect of PDE7 inhibitors in the EAE model of MS, here the TMEV-IDD model was used to test their efficacy in a progressive variant of MS. Mice were subjected to two protocols of TC3.6 administration: on the pre-symptomatic phase and once the disease was established.

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“…However, due to the difficulties to separate beneficial anti‐inflammatory from adverse emetic effects of PDE4 inhibitors, efforts have been focused on finding inhibitors of other PDE that might provide therapeutic alternatives. Special interest has been directed to PDE7 inhibition as an anti‐inflammatory strategy (Smith et al ., ; Giembycz and Smith, ; Castano et al ., ; Jerez et al ., ), and some promising results using PDE7 inhibitors in EAE have been recently reported (Redondo et al ., 2012a; 2012b).…”

Section: Introductionmentioning

confidence: 99%

Comparative assessment of PDE 4 and 7 inhibitors as therapeutic agents in experimental autoimmune encephalomyelitis

Garcı́a

Bravo

Ballester

et al. 2013

British J Pharmacology

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Background and Purpose PDE4 inhibition suppresses experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, side effects hinder PDE4 inhibitors clinical use. PDE7 inhibition might constitute an alternative therapeutic strategy, but few data about the anti‐inflammatory potential of PDE7 inhibitors are currently available. We have used the EAE model to perform a comparative evaluation of PDE4 and PDE7 inhibition as strategies for MS treatment. Experimental Approach Two PDE7 inhibitors, the sulfonamide derivative BRL50481 and the recently described quinazoline compound TC3.6, were assayed to modulate EAE in SJL mice, in comparison with the well‐known PDE4 inhibitor Rolipram. We evaluated clinical signs, presence of inflammatory infiltrates in CNS and anti‐inflammatory markers. We also analysed the effect of these inhibitors on the inflammatory profile of spleen cells in vitro. Key Results TC3.6 prevented EAE with efficacy similar to Rolipram, while BRL50481 had no effect on the disease. Differences between both PDE7 inhibitors are discussed. Data from Rolipram and TC3.6 showed that PDE4 and PDE7 inhibition work through both common and distinct pathways. Rolipram administration caused an increase in IL‐10 and IL‐27 expression which was not found after TC3.6 treatment. On the other hand, both inhibitors reduced IL‐17 levels, prevented infiltration in CNS and increased the expression of the T regulator cell marker Foxp3. Conclusions and Implications These results provide new information about the effects of Rolipram on EAE, underline PDE7 inhibition as a new therapeutic target for inflammatory diseases and show the value of TC3.6 to prevent EAE, with possible consequences for new therapeutic tools in MS.

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Identification in Silico and Experimental Validation of Novel Phosphodiesterase 7 Inhibitors with Efficacy in Experimental Autoimmune Encephalomyelitis Mice

Cited by 24 publications

References 58 publications

Promoting in vivo remyelination with small molecules: a neuroreparative pharmacological treatment for Multiple Sclerosis

Promoting in vivo remyelination with small molecules: a neuroreparative pharmacological treatment for Multiple Sclerosis

PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis

Comparative assessment of PDE 4 and 7 inhibitors as therapeutic agents in experimental autoimmune encephalomyelitis

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