Potent Phosphodiesterase Research Articles

ChemInform Abstract: Synthesis of Quinoline Derivatives: Discovery of a Potent and Selective Phosphodiesterase 5 Inhibitor for the Treatment of Alzheimer′s Disease.

AbstractAll new quinoline derivatives (IV) and (VII) are potent phosphodiesterase 5 inhibitors.

A modular synthesis of novel 4-amino-7,8-dihydro-1,6-naphthyridin-5(6H)-ones as PDE4 inhibitors

A versatile, modular synthetic route to a series of 4-amino-7,8-dihydro-1,6-naphthyridin-5(6H)-ones has been developed. These compounds represent a novel structural class of potent phosphodiesterase IV (PDE4) inhibitors.

ASSA13-03-13 Inhibitory Effects of Vinpocetine on the Progression of Atherosclerosis Are Mediated by Akt/NF-kB Dependent Mechanisms

<h3>Objective</h3> Recent studies have found additional role for vinpocetine, a potent phosphodiesterase type I inhibitor, in anti-proliferation and anti-inflammation of vascular smooth muscle cells and cancer cells via different mechanisms. In this study, we attempted to investigate whether vinpocetine protected against atherosclerotic development in apoE^-/- mice and explore the underlying anti-atherogenic mechanisms in macrophages. <h3>Methods and Results</h3> Vinpocetine markedly decreased atherosclerotic lesion size in apoE^-/- mice measured by oil red O. Masson’s trichrome staining and immunohistochemical analyses revealed that vinpocetine significantly increased the thickness of fibrous cap, reduced the size of lipid-rich necrotic core and attenuated the expression of TNF-alpha and matrix metalloproteinase-9 (MMP-9) within plaque area. <i>In vitro</i> experiments exhibited a significant decrease in monocyte adhension treated with vinpocetine. In parallel with few changes in ox-LDL uptake and foam cell formation, the expression levels of scavenger receptor A and CD 36 were not altered after treatment with vinpocetine. Further, active TNF-alpha, IL-6, monocyte chemoattractant protein-1 and MMP-9 expression induced by ox-LDL was attenuated by vinpocetine in a dose-dependent manner. Similarly, ox-LDL-induced reactive oxygen species were significantly repressed by vinpocetine. Both western blot and luciferase activity assay showed that vinpocetine restored the enhanced Akt, IKK-alpha/beta, IkappaB-alpha phosphorylation and NF-kappaB activity induced by ox-LDL. Cotreatment with LY294002, a specific Akt inhibitor, augmented the inhibitory effects of vinpocetine on IKK-alpha/beta and IkappaB-alpha phosphorylation, suggesting that inhibition of NF-kappaB activity was partly caused by Akt dephosphorylation. Knockdown of PDE1B resulted in an increase of intracellular cGMP contents, however, did not affect Akt, IKK-alpha/beta and IkappaB-alpha phosphorylation. <h3>Conclusions</h3> Vinpocetine exerts anti-atherogenic effects through inhibition of monocyte adhension, oxidative stress and inflammatory response, which are mediated by Akt/NF-kappaB dependent pathway but independent of PDE1 blockade in macrophages.

Synthesis of PDE IV inhibitors. First asymmetric synthesis of two of GlaxoSmithKline's highly potent Rolipram analogues

Asymmetric syntheses of two of GlaxoSmithKline’s highly potent phosphodiesterase IV inhibitors CMPI 1 and CMPO 2 have been accomplished from nitroethane and simple precursors in 8 and 7 steps, respectively. The suggested synthetic strategy involves as a key stage the silylation of enantiopure six-membered cyclic nitronates. In vitro studies of PDE IVB1 inhibition revealed a significant difference in the activity of CMPI 1 and CMPO 2 enantiomers.

ChemInform Abstract: Synthesis of Phosphodiesterase IVb Inhibitors. Part 2. Stereoselective Synthesis of Hexahydro‐3H‐pyrrolo[1,2‐c]imidazol‐3‐one and Tetrahydro‐1H‐pyrrolo[1,2‐c][1,3]oxazol‐3‐one Derivatives.

AbstractStarting from the known nitrone (I), the highly potent phosphodiesterase IVb inhibitors (VII) and (X) are stereoselectively synthesized in an overall yield of 22% and 18%, respectively.

Optical coherence tomography in tadalafil-associated retinal toxicity

Tadalafil (Cialis) is a potent phosphodiesterase type 5 inhibitor that is widely used to treat erectile dysfunction. Phosphodiesterase-5 inhibitors have long been recognized to cause temporary and minor visual changes. We report for the first time a case of visual disturbances due to reversible damage to the parafoveal photoreceptors following the use of tadalafil. The patient was examined using confocal scanning laser ophthalmoscopy combined with spectral domain optical coherence tomography (OCT). Spectral domain OCT of the right eye revealed a hyperreflective dense area and the appearance of a serous retinal detachment (SRD). The photoreceptors' internal segment-outer segment (IS-OS) interface was thickened and markedly hyperreflective without distinguishable deposits. The increased hyperreflectivity of the IS-OS interface created a hyporeflective space behind which mimicked the appearance of a SRD. The use of tadalafil was discontinued and the patient examined 2 months later. Spectral domain OCT revealed disappearance of the dense area and the pseudo-SRD. The associated symptoms resolved rapidly with discontinuation of the drug. Tadalafil use may be associated with reversible damage to the photoreceptors and corresponding visual symptoms.

Synthesis of tetra-substituted pyrroles, a potential phosphodiesterase 4B inhibitor, through nickel(II) chloride hexahydrate catalyzed one-pot four-component reaction

A wide variety of tetra-substituted pyrrole derivatives were synthesized through one-pot four-component condensation reaction of aromatic aldehydes, benzylamines, β-ketoesters, and nitroalkanes in the presence of 10mol% NiCl2·6H2O in good yields. Some of them exhibit properties as potential inhibitors of phosphodiesterase 4B (PDE4B) through docking studies.

Docking studies: &lt;i&gt;In silico&lt;/i&gt; phosphodiesterase inhibitory activity of commercially available flavonoids

The objective of the current study is to evaluate the phosphodiesterase inhibitory activity of flavonoids using in silico docking studies. In silico docking studies were carried out using AutoDock 4.2, based on the Lamarckian genetic algorithm principle. The results showed that all the selected flavonoids showed binding energy ranging between -7.50 kcal/mol to -6.61 kcal/mol when compared with that of the standard (-4.77 kcal/mol). Inhibition constant (3.17 µM to 14.36 µM) and intermolecular energy (-9.29 kcal/mol to -8.70 kcal/mol) of the ligands also coincide with the binding energy. All the selected flavonoids contributed better phosphodiesterase inhibitory activity because of its structural parameters. Benzopyran ring in the flavonoids are majorly contributed its activity. These molecular docking analyses could lead to the further development of potent phosphodiesterase inhibitors for the treatment of inflammatory diseases.

In silico docking studies of phosphodiesterase inhibitory activity of commercially available flavonoids

The primary objective of this study was to investigate the phosphodiesterase inhibitory activity of flavonoids using in silico docking studies. In this perspective, flavonoids like Apigenin, Baicalin, Chrysin, Genistein, Scopoletin and Caffeine were selected. Caffeine, a known phosphodiesterase inhibitor was used as the standard. In silico docking studies were carried out using AutoDock 4.2, based on the Lamarckian genetic algorithm principle. In the docking studies, three important parameters like binding energy, inhibition constant and intermolecular energy were determined. The results showed that all the selected flavonoids showed binding energy ranging between −7.59 kcal/mol to −5.66 kcal/mol when compared with that of the standard (−4.77 kcal/mol). Inhibition constant (2.72 μM to 71.03 μM) and intermolecular energy (−8.49 kcal/mol to −6.26 kcal/mol) of the flavonoids were coincide with the binding energy. All the selected flavonoids contributed phosphodiesterase inhibitory activity because of its functional groups. These molecular docking analyses could lead to the further development of potent phosphodiesterase inhibitors for the treatment of inflammatory disorders.

Abstract 2976: Sildenafil Enhances Neurogenesis And Oligodendrogenesis In The Ischemic Brain Of Aged Mouse

Sildenafil enhances neurogenesis and oligodendrogenesis in the ischemic brain of aged mouse Rui Lan Zhang 1 , Michael Chopp 1,2 Cynthia Roberts 1 , Min Wei 1 , Xinli Wang 1 , Xianshuang Liu 1 , Zheng Gang Zhang 1 Departments of 1 Neurology and Henry Ford Hospital, Detroit, MI, USA 2 Oakland University, Physics Department, Rochester, MI, USA. Background and Purpose: Nestin lineage neural progenitor cells contribute to neurogenesis in adult rodent brain under non-ischemic and ischemic conditions. The present study investigated the effect of sildenafil, a potent phosphodiesterase 5 (PDE5) inhibitor, on nestin lineage neural progenitor cells in the aged mouse after stroke. Methods: Male Nestin-CreER T2 ;R26R-stop-YFP mice at age 16 months were used. Tamoxifen was daily injected for 5 days to activate Cre/loxP system under control of the nestin promoter, leading to permanent YFP labeling of nestin lineage cells. These mice were subjected to permanent middle cerebral artery occlusion (MCAo) 14 days after the last tamoxifen injection. Sildenafil at 10mg/kg (n=11) or saline (n=10) was aadministered daily for 7 days starting 1 day after MCAo. All mice were sacrificed 30 days after MCAo. The number of nestin lineage cells and their fate were analyzed using immunohistochemistry staining. Results: Double immunofluorescent staining confirmed YFP positive cells were nestin positive. Unbiased stereological analysis revealed that sildenafil treatment significantly increased (p&lt;0.05) the number of nestin linage cells in the ischemic subventricular zone (SVZ, 803 ± 28 vs 657 ± 41 in saline), striatum (3739 ± 162 vs 3029 ± 144 in saline), and corpus callosum (2957 ± 86 vs 2578 ± 117 in saline). Phenotype analysis showed that sildenafil substantially augmented the number of nestin lineage neuroblasts identified by doublecortin positive cells (19.4 ± 1.6 % vs 12.9 ± 1.1 % in saline), nestin lineage mature neurons measured by NeuN (6.2 ± 0.8 % vs 3.0 ± 0.6 %) and calbindin (10.8 ± 0.9 vs 7.2 ± 1.1) positive cells in the ischemic striatum. Sildenafil also significantly (p&lt;0.05) increased the number of nestin lineage oligodendrocytes measured by 2’, 3’-cyclic nucleotide, 3’-phosphodiesterase (CNPase) positive cells in ischemic striatum (21.3 ± 1.2 vs 19.9 ± 1.4 in saline) and corpus callosum (18.9 ± 1.4 vs 14.4 ± 1.3 in saline). Conclusion: Our data demonstrate that sildenafil enhances neurogenesis and oligodendrogenesis in the ischemic brain of the aged mouse, which could contribute sildenafil-improved neurological outcome after stroke which we have demonstrated.

Discovery of 4-hydroxy-1,6-naphthyridine-3-carbonitrile derivatives as novel PDE10A inhibitors

A series of 1,6-naphthyridine-based compounds was synthesized as potent phosphodiesterase 10A (PDE10A) inhibitors. Structure-based chemical modifications of the discovered chemotype served to further improve potency and selectivity over DHODH, laying the foundation for future optimization efforts.

ChemInform Abstract: Synthesis and Biological Activity of Pyrido[3′,2′:4,5]furo[3,2‐d]pyrimidine Derivatives as Novel and Potent Phosphodiesterase Type 4 Inhibitors.

AbstractTitle compounds (X) and (XIV) are tested for phosphodiesterase type 4 (PDE4) inhibitory activity, with the potential to treat asthma and chronic obstructive pulmonary disease.

Computational drug discovery of potential phosphodiesterase inhibitors using in silico studies

ObjectiveTo evaluate the phosphodiesterase inhibitory activity of flavonoids using in silico docking studies. MethodsIn this perspective, flavonoids like Aromadedrin, Biochanin, Eriodictyol, Isorhamnetin, and Okanin were selected. Caffeine, a known phosphodiesterase inhibitor was used as the standard. In silico docking study, was carried out to identify the inhibiting potential of the selected flavonoids against phosphodiesterase enzyme using AutoDock 4.2. The basic principle employed in the AutoDock 4.2 was Lamarckian genetic algorithm. ResultsDocking results showed that all the selected flavonoids showed binding energy ranging between −7.57 kcal/mol to −5.79 kcal/mol when compared with that of the standard (−4.77 kcal/mol). Intermolecular energy (−9.06 kcal/mol to −8.17 kcal/mol) and inhibition constant (2.82 μmol to 57.41 μmol) of the ligands also coincide with the binding energy. ConclusionsEriodictyol contributed better phosphodiesterase inhibitory activity because of its structural parameters. Further investigations on the above compounds and in vivo studies are necessary to develop potential chemical entities for the prevention and treatment of inflammatory disorders.

6-Nitrobenzimidazole derivatives: Potential phosphodiesterase inhibitors: Synthesis and structure–activity relationship

6-Nitrobenzimidazole derivatives (1–30) synthesized and their phosphodiesterase inhibitory activities determined. Out of thirty tested compounds, ten showed a varying degrees of phosphodiesterase inhibition with IC50 values between 1.5±0.043 and 294.0±16.7μM. Compounds 30 (IC50=1.5±0.043μM), 1 (IC50=2.4±0.049μM), 11 (IC50=5.7±0.113μM), 13 (IC50=6.4±0.148μM), 14 (IC50=10.5±0.51 μM), 9 (IC50=11.49±0.08μM), 3 (IC50=63.1±1.48μM), 10 (IC50=120.0±4.47μM), and 6 (IC50=153.2±5.6μM) showed excellent phosphodiesterase inhibitory activity, much superior to the standard EDTA (IC50=274±0.007μM), and thus are potential molecules for the development of a new class of phosphodiesterase inhibitors. A structure–activity relationship is evaluated. All compounds are characterized by spectroscopic parameters.

Phosphodiesterase I-Inhibiting Diels-Alder Adducts from the Leaves ofMorus mesozygia

A new 2-arylbenzofuran derivative, (+)-dimethylsmoracin O (1), and three new Diels-Alder type adducts, mesozygins A–C (2–4), in addition to eight known compounds, artonin I (5), chalcomaracin (6), norartocarpetin (7), moracin L (8), mulberrofuran F (9), moracin M (10), moracin C (11), and morachalcone A (12),were isolated from the leaves of Morus mesozygia Stapf. Structures were elucidated by spectroscopic data analyses. Compounds 2-7 displayed a potent phosphodiesterase I inhibitory activity.

Synthesis of phosphodiesterase IVb inhibitors 2. Stereoselective synthesis of hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one and tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one derivatives

The total stereoselective synthesis of two highly potent phosphodiesterase IVb inhibitors from nitroethane, isovanillin, and ethyl vinyl ether was developed. The compounds obtained are the derivatives of hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one and tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one. The strategy proposed involves silylation of six-membered cyclic nitronates as a key step leading to 5,6-dihydro-4H-1,2-oxazines with the group CH2FG (FG = N3 or OH) at the C(3) atom.

Docking-based CoMFA and CoMSIA analyses of tetrahydro-β-carboline derivatives as type-5 phosphodiesterase inhibitors

Tetrahydro-β-carboline derivatives (THBCs) have been identified as a class of potent Type-5 Phosphodiesterase (PDE5) inhibitors, showing benefits for the treatment of erectile dysfunction and also bearing anticancer properties. A computational strategy based on molecular docking studies, followed by docking-based Comparative Molecular Fields Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA), has been used to elucidate the atomic details of the PDE5/THBC interactions and to identify the most important features impacting the THBC PDE5 inhibitory activity. The final CoMSIA model resulted to be the more predictive, showing rncv2 = 0.96, rcv2 = 0.688, SEE = 0.248, F = 104.800, and r2pred = 0.78. The results allowed us to obtain useful information for the design of new THBC analogues, potentially acting as PDE5 inhibitors, and to predict their potency prior to synthesis.

Combining 2D and 3D in silico methods for rapid selection of potential PDE5 inhibitors from multimillion compounds’ repositories: biological evaluation

Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost-effective approach when starting new drug discovery projects. If structures of active compounds are available rapid 2D similarity search can be performed on multimillion compounds' databases. This in silico approach can be combined with physico-chemical parameter filtering based on the property space of the active compounds and 3D virtual screening if the structure of the target protein is available. A multi-step virtual screening procedure was developed and applied to select potential phosphodiesterase 5 (PDE5) inhibitors in real time. The combined 2D/3D in silico method resulted in the identification of 14 novel PDE5 inhibitors with <1 μMIC(50) values and the hit rate in the second in silico selection and in vitro screening round exceeded the 20%.

Synthesis of PDE IVb Inhibitors. 1. Asymmetric Synthesis and Stereochemical Assignment of (+)- and (−)-7-[3-(Cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one

Asymmetric synthesis of GlaxoSmithKline's highly potent phosphodiesterase inhibitor 1 has been accomplished in nine steps and 16% overall yield. The original strategy suggested involves as a key step the silylation of enantiopure six-membered cyclic nitronates 4 obtained by a highly stereoselective [4 + 2]-cycloaddition of an appropriate nitroalkene 5 to trans-1-phenyl-2-(vinyloxy)cyclohexane. Functionalization of the resulting 5,6-dihydro-4H-1,2-oxazine and subsequent stereoselective reduction of 1,2-oxazine ring in intermediate 2 furnished the pyrrolizidinone framework with the recovery of chiral auxiliary alcohol.

1,1-Diarylalkenes as anticancer agents: Dual inhibitors of tubulin polymerization and phosphodiesterase 4

A series of 1,1-diarylalkene derivatives were prepared to optimize the properties of CC-5079 (1), a dual inhibitor of tubulin polymerization and phosphodiesterase 4 (PDE4). By using the 3-ethoxy-4-methoxyphenyl PDE4 pharmacophore as one of the aromatic rings, a significant improvement in PDE4 inhibition was achieved. Compound 28 was identified as a dual inhibitor with potent PDE4 (IC50=54nM) and antitubulin activity (HCT-116 IC50=34nM and tubulin polymerization IC50 ∼1μM). While the nitrile group at the alkene terminus was generally required for potent antiproliferative activity, its replacement was tolerated if there was a hydroxyl or amino group on one of the aryl rings. Conveniently, this group could also serve as a handle for amino acid derivatization to improve the compounds’ solubility. The glycinamide analog 45 showed significant efficacy in the HCT-116 xenograft model, with 64% inhibition of tumor growth upon dosing at 20mg/kg qd.