Characterization of the First Potent and Selective PDE9 Inhibitor Using a cGMP Reporter Cell Line

Wunder, Frank; Tersteegen, Adrian; Rebmann, Annegret; Erb, Christina; Fahrig, Thomas; Hendrix, Martin

doi:10.1124/mol.105.017608

Cited by 133 publications

(110 citation statements)

References 24 publications

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“…Development 136 (11) PDE9A was only effective in causing meiotic resumption if PDE3A in the oocyte was active; in the presence of the PDE3 inhibitor milrinone (Lugnier, 2006), which does not inhibit PDE9A (Wunder et al, 2005), meiotic resumption in response to PDE9A injection was reversibly inhibited (Fig. 8C).…”

Section: Research Articlementioning

confidence: 99%

Cyclic GMP from the surrounding somatic cells regulates cyclic AMP and meiosis in the mouse oocyte

et al. 2009

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Mammalian oocytes are arrested in meiotic prophase by an inhibitory signal from the surrounding somatic cells in the ovarian follicle. In response to luteinizing hormone (LH), which binds to receptors on the somatic cells, the oocyte proceeds to second metaphase, where it can be fertilized. Here we investigate how the somatic cells regulate the prophase-to-metaphase transition in the oocyte, and show that the inhibitory signal from the somatic cells is cGMP. Using FRET-based cyclic nucleotide sensors in follicleenclosed mouse oocytes, we find that cGMP passes through gap junctions into the oocyte, where it inhibits the hydrolysis of cAMP by the phosphodiesterase PDE3A. This inhibition maintains a high concentration of cAMP and thus blocks meiotic progression. LH reverses the inhibitory signal by lowering cGMP levels in the somatic cells (from ~2 μM to ~80 nM at 1 hour after LH stimulation) and by closing gap junctions between the somatic cells. The resulting decrease in oocyte cGMP (from ~1 μM to ~40 nM) relieves the inhibition of PDE3A, increasing its activity by ~5-fold. This causes a decrease in oocyte cAMP (from ~700 nM to ~140 nM), leading to the resumption of meiosis.

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Section: Research Articlementioning

confidence: 99%

Cyclic GMP from the surrounding somatic cells regulates cyclic AMP and meiosis in the mouse oocyte

et al. 2009

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“…with an IC 50 ϳ60 nM has been produced by Bayer (414). It has strong selectivity for PDE9 with much weaker potencies toward other PDEs: PDE1 and PDE11 (IC 50 values for PDE1 ϭ 1,400 nM, PDE11 ϭ 2,600 nM, and for PDEs 2A, 3B, 4B, 7B, 8A, and 10A Ͼ4000 nM) (414).…”

Section: Pde9 Inhibitorsmentioning

confidence: 99%

“…It has strong selectivity for PDE9 with much weaker potencies toward other PDEs: PDE1 and PDE11 (IC 50 values for PDE1 ϭ 1,400 nM, PDE11 ϭ 2,600 nM, and for PDEs 2A, 3B, 4B, 7B, 8A, and 10A Ͼ4000 nM) (414). Vardenafil inhibits PDE9 (IC 50 ϳ600 -3,400 nM) with a much weaker potency than that for PDE5 (IC 50 ϳ0.1-0.4 nM) (75,105).…”

Section: Pde9 Inhibitorsmentioning

confidence: 99%

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

Francis

Blount

Corbin

2011

Physiological Reviews

567

546

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The superfamily of cyclic nucleotide (cN) phosphodiesterases (PDEs) is comprised of 11 families of enzymes. PDEs break down cAMP and/or cGMP and are major determinants of cellular cN levels and, consequently, the actions of cN-signaling pathways. PDEs exhibit a range of catalytic efficiencies for breakdown of cAMP and/or cGMP and are regulated by myriad processes including phosphorylation, cN binding to allosteric GAF domains, changes in expression levels, interaction with regulatory or anchoring proteins, and reversible translocation among subcellular compartments. Selective PDE inhibitors are currently in clinical use for treatment of erectile dysfunction, pulmonary hypertension, intermittent claudication, and chronic pulmonary obstructive disease; many new inhibitors are being developed for treatment of these and other maladies. Recently reported x-ray crystallographic structures have defined features that provide for specificity for cAMP or cGMP in PDE catalytic sites or their GAF domains, as well as mechanisms involved in catalysis, oligomerization, autoinhibition, and interactions with inhibitors. In addition, major advances have been made in understanding the physiological impact and the biochemical basis for selective localization and/or recruitment of specific PDE isoenzymes to particular subcellular compartments. The many recent advances in understanding PDE structures, functions, and physiological actions are discussed in this review.

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“…The structure of BAY 63-2521 is provided in supplemental figure 1. A possible inhibition of phosphodiesterases (PDE) was investigated in a PDE activity assay as described previously [17].…”

Section: Immunohistochemical Stainingmentioning

confidence: 99%

Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension

Schermuly

Jp²,

Pullamsetti³

et al. 2008

Eur Respir J

218

168

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Alterations of the nitric oxide receptor, soluble guanylate cyclase (sGC) may contribute to the pathophysiology of pulmonary arterial hypertension (PAH). In the present study, the expression of sGC in explanted lung tissue of PAH patients was studied and the effects of the sGC stimulator BAY 63-2521 on enzyme activity, and haemodynamics and vascular remodelling were investigated in two independent animal models of PAH.Strong upregulation of sGC in pulmonary arterial vessels in the idiopathic PAH lungs compared with healthy donor lungs was demonstrated by immunohistochemistry. Upregulation of sGC was detected, similarly to humans, in the structurally remodelled smooth muscle layer in chronic hypoxic mouse lungs and lungs from monocrotaline (MCT)-injected rats. BAY 63-2521 is a novel, orally available compound that directly stimulates sGC and sensitises it to its physiological stimulator, nitric oxide. Chronic treatment of hypoxic mice and MCT-injected rats, with fully established PAH, with BAY 63-2521 (10 mg?kg) partially reversed the PAH, the right heart hypertrophy and the structural remodelling of the lung vasculature.Upregulation of soluble guanylate cyclase in pulmonary arterial smooth muscle cells was noted in human idiopathic pulmonary arterial hypertension lungs and lungs from animal models of pulmonary arterial hypertension. Stimulation of soluble guanylate cyclase reversed right heart hypertrophy and structural lung vascular remodelling. Soluble guanylate cyclase may thus offer a new target for therapeutic intervention in pulmonary arterial hypertension.KEYWORDS: BAY 63-2521, cardiovascular diseases, nitric oxide, pharmacology, pulmonary arterial hypertension, smooth muscle P ulmonary arterial hypertension (PAH) is a disabling disease, with high mortality, characterised by sustained elevation in pulmonary arterial pressure (Ppa) and pulmonary vascular remodelling due to proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) [1]. Imbalance of vasodilatory and vasoconstrictive mediators has been implicated in these changes. Reduced urinary excretion of prostaglandin (PG)I 2 and augmented excretion of thromboxane metabolites were found in patients with idiopathic PAH (IPAH) [2], and immunohistological studies have shown reduced expression of PGI 2 synthase in the pulmonary vessels originating from those patients [3]. Another important mediator in the regulation of vascular tone is nitric oxide (NO), which is synthesised by NO synthases. Local NO production from endothelium and epithelium regulates pulmonary perfusion, depending on alveolar ventilation to assure optimised ventilation/perfusion distribution [4][5][6]. In patients with IPAH, it has been reported that the expression of endothelial NO synthase is downregulated [7], while other reports show an upregulation in plexiform lesions of IPAH patients [8]. However, little is known about the expression and regulation of soluble guanylate cyclase (sGC) which operates as a receptor for NO. Typically, sGC is found as a hetero...

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Characterization of the First Potent and Selective PDE9 Inhibitor Using a cGMP Reporter Cell Line

Cited by 133 publications

References 24 publications

Cyclic GMP from the surrounding somatic cells regulates cyclic AMP and meiosis in the mouse oocyte

Cyclic GMP from the surrounding somatic cells regulates cyclic AMP and meiosis in the mouse oocyte

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension

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