Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety

Burgin, Alex B.; Magnússon, Ólafur Þ.; Singh, Jasbir; Witte, Pam; Staker, Bart L.; Björnsson, Jón Már; Þorsteinsdóttir, Margrét; Hrafnsdottir, Sigrun; Hagen, Timothy J.; Kiselyov, Alex S.; Stewart, Lance; Gurney, Mark E.

doi:10.1038/nbt.1598

Cited by 343 publications

(509 citation statements)

References 50 publications

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“…Interestingly, the occurrence of emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, is also significantly reduced by D159687 (6). 146 This strategy of PDE4 modulation may therefore lead to the development of pharmacotherapeutic compounds in the near future that will ultimately become available to the patient.…”

Section: +mentioning

confidence: 99%

“…In addition to the selective PDE4D inhibitor GEBR-7B (5) (see section 2), 145 DeCode Genetics has used structural information (PDB: 3IAD) 139 to develop a series of PDE4 allosteric modulators that serve as a molecular glue to close a regulatory domain, in this case acting as a "lid" over the PDE4 catalytic site. 146 These compounds do not completely abolish PDE4 enzymatic activity in cellular and in vivo models. Interestingly, the occurrence of emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, is also significantly reduced by D159687 (6).…”

Section: +mentioning

confidence: 99%

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Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

García‐Osta¹,

Cuadrado‐Tejedor²,

García‐Barroso³

et al. 2012

ACS Chem. Neurosci.

219

177

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Alzheimer's disease (AD) is the most common form of dementia among the elderly. In AD patients, memory loss is accompanied by the formation of beta-amyloid plaques and the appearance of tau in a pathological form. Given the lack of effective treatments for AD, the development of new management strategies for these patients is critical. The continued failure to find effective therapies using molecules aimed at addressing the anti-beta amyloid pathology has led researchers to focus on other non-amyloid-based approaches to restore memory function. Promising non-amyloid related candidate targets include phosphosdiesterases (PDEs), and indeed, Rolipram, a specific PDE4 inhibitor, was the first compound found to effectively restore cognitive deficits in animal models of AD. More recently, PDE5 inhibitors have also been shown to effectively restore memory function. Accordingly, inhibitors of other members of the PDE family may also improve memory performance in AD and non-AD animal models. Hence, in this review, we will summarize the data supporting the use of PDE inhibitors as cognitive enhancers and we will discuss the possible mechanisms of action underlying these effects. We shall also adopt a medicinal chemistry perspective that leads us to propose the most promising PDE candidates on the basis of inhibitor selectivity, brain distribution, and mechanism of action.

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Section: +mentioning

confidence: 99%

Section: +mentioning

confidence: 99%

Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

García‐Osta¹,

Cuadrado‐Tejedor²,

García‐Barroso³

et al. 2012

ACS Chem. Neurosci.

219

177

View full text Add to dashboard Cite

show abstract

“…When these findings are confirmed by mapping of the CaMKII phosphorylation sites, they will provide evidence of a novel regulatory domain in PDE4. Given the hypothesis that the PDE4 catalytic pocket is regulated by a "capping helix" of the upstream conserved region 2 (UCR2) (32), it will be important to determine the effect of this additional phosphorylation on the positioning of this critical domain.…”

Section: +mentioning

confidence: 99%

A CaMKII/PDE4D negative feedback regulates cAMP signaling

Mika

Richter

Conti

2015

Proc. Natl. Acad. Sci. U.S.A.

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cAMP production and protein kinase A (PKA) are the most widely studied steps in β-adrenergic receptor (βAR) signaling in the heart; however, the multifunctional Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is also activated in response to βAR stimulation and is involved in the regulation of cardiac excitation-contraction coupling. Its activity and expression are increased during cardiac hypertrophy, in heart failure, and under conditions that promote arrhythmias both in animal models and in the human heart, underscoring the clinical relevance of CaMKII in cardiac pathophysiology. Both CaMKII and PKA phosphorylate a number of protein targets critical for Ca 2+ handling and contraction with similar, but not always identical, functional consequences. How these two pathways communicate with each other remains incompletely understood, however. To maintain homeostasis, cyclic nucleotide levels are regulated by phosphodiesterases (PDEs), with PDE4s predominantly responsible for cAMP degradation in the rodent heart. Here we have reassessed the interaction between cAMP/PKA and Ca 2+ /CaMKII signaling. We demonstrate that CaMKII activity constrains basal and βAR-activated cAMP levels. Moreover, we show that these effects are mediated, at least in part, by CaMKII regulation of PDE4D. This regulation establishes a negative feedback loop necessary to maintain cAMP/CaMKII homeostasis, revealing a previously unidentified function for PDE4D as a critical integrator of cAMP/PKA and Ca elevation throughout the cell promotes myofilament sliding, which generates contractile force. This process is highly regulated by positive and negative regulatory circuits, the most critical being the sympathetic nervous system that acts via activation of the β-adrenergic (βAR)/cAMP/PKA signaling pathway. During βAR stimulation, PKA phosphorylates and activates key proteins involved in ECC and Ca 2+ handling. These proteins include L-type Ca 2+ channels and ryanodine receptors (RyR), leading to enhanced Ca 2+ influx and consequent sarcoplasmic reticulum (SR) Ca 2+ release; phospholamban (PLB), increasing SR Ca 2+ uptake by the Ca 2+ ATPase (SERCA), thereby accelerating cardiac relaxation; and contractile proteins, increasing cell contraction. Collectively, these events produce the typical inotropic and lusitropic effects of βAR stimulation (1).This βAR/cAMP/PKA pathway is only one of the components involved in regulating cardiac function, however. Data accumulated in the last decade have revealed that Ca 2+

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“…Several strategies are available to avoid such problems. One possibility might be to develop subtype-selective PDE4-inhibitors since it has become dogma that side-effects like nausea are due exclusively to inhibition of the PDE4D isoenzymes -however, this viewpoint in not universally shared [15] and the recent discovery of selective brain-penetrant PDE4-inhibitors that are devoid of emesis [54] adds further weight against avoiding the targeting of PDE4D, particularly as this enzyme subtype is expressed in cells of interest to COPD.…”

Section: Beyond Roflumilastmentioning

confidence: 99%

PDE4-inhibitors: A novel, targeted therapy for obstructive airways disease

Diamant

Spina

2011

Pulmonary Pharmacology & Therapeutics

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SummaryRoflumilast is a selective once daily, oral phosphodiesterase-4 inhibitor that has recently been registered in all European Union countries as novel targeted therapy for COPD, while FDA approval for the USA market is expected in 2011. In several phase III trials in patients with moderate to (very) severe COPD and in patients with symptoms of chronic bronchitis and recurrent exacerbations, roflumilast showed sustained clinical efficacy by improving lung function and by reducing exacerbation rates. These beneficial effects have also been demonstrated when added to long-acting bronchodilators (both LABA and LAMA), underscoring the anti-inflammatory activity of roflumilast in COPD. Pooled data analysis showed overall mild to moderate, mostly self-limiting adverse events, mainly consisting of nausea, diarrhea and weight loss. In this review we discuss the results of the 4 registration studies showing promising effects of roflumilast in COPD and provide an overview of the topics that still need to be addressed. keywords: PDE4-inhibitor, roflumilast, clinical trials, chronic obstructive airways disease 3

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Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety

Cited by 343 publications

References 50 publications

Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

A CaMKII/PDE4D negative feedback regulates cAMP signaling

PDE4-inhibitors: A novel, targeted therapy for obstructive airways disease

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