Antithrombotic Activity of NSP-513, a Novel Selective Phosphodiesterase 3 Inhibitor, on Femoral Arterial Thrombosis Induced by Physical Stenosis and Electrical Current: Comparison of Antithrombotic and Hemodynamic Effects

Hirose, Hiroyasu; Mashiko, Satoshi; Kimura, Toshifumi; Ishida, Fumiaki; Mochizuki, Nobuo; Nishibe, Tadayuki; Nishikibe, Masaru

doi:10.1097/00005344-200004000-00012

Cited by 10 publications

(4 citation statements)

References 25 publications

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“…[7][8][9][10][11][12] Animal models in which pulmonary thromboembolism is induced by platelet agonists have demonstrated that inhibition of PDE3A reduces the rate of mortality by inhibiting thromboembolism. 31,32 PDE3A inhibitors also reduce in vivo thrombosis induced by electrical stimulation of the blood vessel wall. This conclusion is based on measurements of thrombus-induced changes in blood flow and measurements of the weight of resultant thrombus following electrical stimulation.…”

Section: Discussionmentioning

confidence: 99%

Initial accumulation of platelets during arterial thrombus formation in vivo is inhibited by elevation of basal cAMP levels

Sim

Merrill-Skoloff

Furie

et al. 2004

Blood

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Platelet accumulation at sites of vascular injury is the primary event in arterial thrombosis. Initial platelet accrual into thrombi is mediated by interactions of platelet adhesion receptors with ligands on the injured endothelium or in the subendothelial matrix. The role of intracellular signals in initial platelet accumulation at sites of endothelial injury, however, is the subject of debate. We have used a newly discovered inhibitor of phosphodiesterase 3A (PDE3A) and the well-characterized PDE3A inhibitor, cilostazol, to modulate 3,5-cyclic adenosine monophosphate (cAMP) levels in an in vivo model that enables the kinetic analysis of platelet accumulation. These studies demonstrate that elevation of basal cAMP levels results in an overall decline in platelet accumulation at the site of vascular injury. In particular, the initial rate of accumulation of platelets is inhibited by elevation of cAMP. Analysis of the kinetics of individual platelets at injury sites using intravital microscopy demonstrates that cAMP directs the rate at which platelets attach to and detach from thrombi. These studies demonstrate that cAMP in circulating platelets controls attachment to and detachment from sites of arteriolar injury. Thus, the status of the intracellular signaling machinery prior to engagement of platelet receptors influences the rate of platelet accumulation during thrombus formation. ( IntroductionWhile it is well established that adhesion molecules affect signaling events that lead to platelet activation, it is also possible that intracellular signals present in circulating platelets prior to interactions with thrombi affect the ability of platelets to incorporate into thrombi. [1][2][3][4][5] The role of intracellular signaling in controlling the initial accumulation of platelets into thrombi at sites of vascular injury, however, is largely unexplored. Critical roles for 3Ј,5Ј-cyclic adenosine monophosphate (cAMP), cAMPdependent protein kinase (protein kinase A [PKA]), and phosphodiesterase 3A (PDE3A) in thrombus formation have been suggested in both in vivo models 6 and clinical studies of arterial thrombosis. [7][8][9][10][11][12] Cyclic AMP inhibits platelets by activating PKA, which phosphorylates several substrates important for the activation of platelets. PDE3A hydrolyzes cAMP to 5Ј-AMP. As a result, PDE3A opposes PKA-mediated platelet inhibition. Phosphorylation of several intracellular PKA substrates is associated with the inhibition of multiple platelet functions. For example, IP 3 receptor phosphorylation by PKA is proposed to downregulate calcium release from intracellular stores. 13,14 PKA phosphorylation of G ␣13 causes inhibition of the RhoA/Rho kinase pathway. 15 PKA inhibits signaling to the cytoskeleton 16,17 and may stabilize the resting cytoskeleton by phosphorylation of cytoskeletal proteins such as actinbinding protein 18 and caldesmon. 19 In addition to the phosphorylation of these intracellular substrates, PKA also inhibits other signaling events such as mitogen-activated protein kinas...

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Section: Discussionmentioning

confidence: 99%

Initial accumulation of platelets during arterial thrombus formation in vivo is inhibited by elevation of basal cAMP levels

Sim

Merrill-Skoloff

Furie

et al. 2004

Blood

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“…For example, a lipophilic inhibitor might more readily access a membrane bound isozyme. 20 NSP-513 39 [117] a IC50 data has been obtained from a variety of sources and under differing conditions, including enzyme sources. Information is provided as a qualitative guide only.…”

Section: Tissue/cell Specific Expression and Subcellular Localizationmentioning

confidence: 99%

“…With the large body of reported compounds to choose from, Edmondsen et al [116] pursued the pyridazinone core common to many agents including imazodan and siguazodan -with a first glimpse of selectivity in acylated compounds; moreover by elaboration in analogous fashion to the compound NSP-513, 20 (Fig. 3) [117], compounds such as 21 with 7 fold selectivity for PDE3B could be derived. (IC50 v PDE3B = 0.19 nM) Other substitutions led to extraordinarily potent compounds such as 22 (IC50 v PDE3B = 0.049 nM) or slightly improved selectivity 23 (~10 fold, IC50 v PDE3B = 4.8 nM).…”

Section: Development Of Pde3b Selective Ligandsmentioning

confidence: 99%

Re-Discovering PDE3 Inhibitors - New Opportunities for a Long Neglected Target

Thompson¹,

Manganiello²,

Degerman

2007

CTMC

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The PDE3 enzymes or "low Km cGMP-inhibited phosphodiesterases" have long been established as important mediators of cellular physiology, and synthetic PDE3 inhibitors have been critical to the delineation of the enzymes' roles. Yet despite decades of progress on the biology of these enzymes, the medicinal chemistry landscape relating to PDE3 inhibitors has remained essentially unchanged since the mid 1990's. Up until then the field was at the cutting edge of drug design; without the tools of molecular and structural biology, molecules of high potency were being achieved using logical pharmacophore models and lead modification. Yet virtually all the impetus went out of this area on the back of failures at the clinic and PDE3 as a therapeutic target largely fell out of favour. A decade later and with the "new" technologies of structural and molecular biology breathing new life into PDE3 research in general, PDE3 inhibitors are sought for target validation in an array of therapeutic applications. In this review, we examine the current state of PDE3 research; firstly we summarize the structural and functional properties of PDE3 enzymes with particular attention to the heterogeneity within this class of enzymes which differ markedly in expression, localisation and means of regulation across various tissue types. It is the structural and functional complexity of the PDE3 enzymes that underpins the re-emergence of PDE3s roles as targets for drug design. We then look at past clinical evaluation of PDE3 inhibitors that occurred without that information and which may have had a significant bearing on the outcome of those drug discovery efforts. Finally we look at current approaches to the design of PDE3 inhibitors which utilize that historic data but also incorporate new inputs from structural biology and combinatorial chemistry.

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“…Cilostazol is a selective phosphodiesterase type III inhibitor that suppresses cAMP degradation. In dogs, cilaostazol has been shown to increase heart rate, ventricular automaticity, myocardial contractility and coronary flow [129,130]. The anti-platelet effects are reversible and the drug inhibits the platelet aggregation by typical inducers such as thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress [128].…”

Section: Pentoxifylline/cilostazolmentioning

confidence: 99%