L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition

Huang, Zheng; Dias, Rebecca; Jones, Tom R.; Liu, S.; Styhler, Angela; Claveau, David; Otu, Franklin; Ng, Kim T.; Laliberté, France; Zhang, L.; Goetghebeur, Pascal; Abraham, William M.; Macdonald, D.D.; Dubé, Daniel; Gallant, Michel; Lacombe, Patrick; Girard, Yves; Young, Robert N.; Turner, Mervyn J.; Nicholson, Donald W.; Mancini, Joseph A.

doi:10.1016/j.bcp.2007.03.010

Cited by 27 publications

(20 citation statements)

References 36 publications

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“…102 The PDE4 inhibitors MEM1018 and MEM1091 influence NMDA receptor-dependent memory, 103 and other selective PDE4 inhibitors including rolipram have been shown to influence memory and cognition in several studies. [103][104][105][106][107][108][109][110] Moreover, translation of specific PDE4 isoforms is regulated during long-term potentiation 111 and in NMDA-receptor-mediated memory functions. 112 PDE4s also influence myelination, 113 and rolipram has been shown to reduce demyelination and CNS inflammation, 114 and to promote axon regrowth and myelination in vivo.…”

Section: Pde4b As a Risk Factor For Psychiatric Illness: Interaction mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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Section: Pde4b As a Risk Factor For Psychiatric Illness: Interaction mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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“…Importantly, memory- and cognition-enhancing effects are not only observed with Rolipram, but also with structurally unrelated PDE4 inhibitors [31-33,39,53], suggesting that these are class effects and result directly from inactivation of PDE4s. This conclusion is further confirmed by studies employing genetic downregulation or ablation of PDE4 subtypes, in particular PDE4D, as described in more detail below.…”

Section: The Pde4 Family As a Target For Cognition Enhancementmentioning

confidence: 99%

PDE4 as a target for cognition enhancement

Richter

Menniti

Zhang

et al. 2013

Expert Opinion on Therapeutic Targets

120

105

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Introduction The second messengers cAMP and cGMP mediate fundamental aspects of brain function relevant to memory, learning and cognitive functions. Consequently, cyclic nucleotide phosphodiesterases (PDEs), the enzymes that inactivate the cyclic nucleotides, are promising targets for the development of cognition-enhancing drugs. Areas covered PDE4 is the largest of the eleven mammalian PDE families. This review covers the properties and functions of the PDE4 family, highlighting procognitive and memory-enhancing effects associated with their inactivation. Expert opinion PAN-selective PDE4 inhibitors exert a number of memory- and cognition-enhancing effects and have neuroprotective and neuroregenerative properties in preclinical models. The major hurdle for their clinical application is to target inhibitors to specific PDE4 isoforms relevant to particular cognitive disorders to realize the therapeutic potential while avoiding side effects, in particular emesis and nausea. The PDE4 family comprises four genes, PDE4A-D, each expressed as multiple variants. Progress to date stems from characterization of rodent models with selective ablation of individual PDE4 subtypes, revealing that individual subtypes exert unique and non-redundant functions in the brain. Thus, targeting specific PDE4 subtypes, as well as splicing variants or conformational states, represents a promising strategy to separate the therapeutic benefits from the side effects of PAN-PDE4 inhibitors.

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“…The narrow therapeutic index (TI) of rolipram prompted many investigators to pursue other strategies to separate the emetic liabilities from the beneficial effects. Such strategies have included the development of selective subtype PDE4D and PDE4B active site inhibitors [36], [38], [50]–[52], as well as the development of allosteric negative modulators (NAMs) of PDE4D [36]. In particular, a recent manuscript described the development of PDE4D NAMs with much improved TI over rolipram [36], [53], [54], due to their mechanism of inhibition (novel binding mode to the UCR2 domain of PDE4D7) and lack of full antagonism profile [36].…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Selective PDE4D Negative Allosteric Modulators in the Object Retrieval Task in Female Cynomolgus Monkeys (Macaca fascicularis)

Sutcliffe¹,

Beaumont

Watson³

et al. 2014

PLoS ONE

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Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat disorders associated with dysfunction of these circuits. The phosphodiesterase (PDE) type 4 inhibitor rolipram has shown significant pro-cognitive effects in neurological disease models, both in rodents and primates. However, competitive non-isoform selective PDE4 inhibitors have a low therapeutic index which has stalled their clinical development. Here, we demonstrate the pro-cognitive effects of selective negative allosteric modulators (NAMs) of PDE4D, D159687 and D159797 in female Cynomolgous macaques, in the object retrieval detour task. The efficacy displayed by these NAMs in a primate cognitive task which engages the corticostriatal circuitry, together with their suitable pharmacokinetic properties and safety profiles, suggests that clinical development of these allosteric modulators should be considered for the treatment of a variety of brain disorders associated with cognitive decline.

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L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition

Cited by 27 publications

References 36 publications

The DISC locus in psychiatric illness

The DISC locus in psychiatric illness

PDE4 as a target for cognition enhancement

Efficacy of Selective PDE4D Negative Allosteric Modulators in the Object Retrieval Task in Female Cynomolgus Monkeys (Macaca fascicularis)

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