PDE5 inhibitors – pharmacology and clinical applications 20 years after sildenafil discovery

Ke, Andersson

doi:10.1111/bph.14205

Cited by 361 publications

(176 citation statements)

References 77 publications

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“…This extract was discarded. A second extraction was performed with 600 mL of diethyl ether to obtain osajin (1), and the other isoflavone pomiferin. The mixture obtained was evaporated at reduced pressure to almost dryness, and then diluted with 500 mL of ethanol.…”

Section: Chemistrymentioning

confidence: 99%

“…The inhibitors of phosphodiesterase 5 (PDE5) are currently used in the clinical practice for the treatment of erectile dysfunction, pulmonary hypertension, and lower urinary symptoms [1], but several other potential therapeutic applications are emerging [1,2]. Scientific literature is particularly prolific for what concerns natural compounds or nature-inspired molecules showing inhibitory activity on PDE5 [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, we improved the extraction conditions of the natural scaffold and expanded the variety of chemical modifications with the aim of further improving the efficacy against PDE5. The procedures for the extraction of osajin (1) from Maclura pomifera and the reaction conditions for the isolation of compound 2 are here described. NMR, mass spectrometry, HPLC and ultra-violet (UV) data are also reported.…”

Section: Introductionmentioning

confidence: 99%

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5-Hydroxy-3-(4-hydroxyphenyl)-8,8-dimethyl-6-(3-methylbut-2-enyl)pyrano[2,3-h]chromen-4-one

Ribaudo

Ongaro

Zagotto

2018

Molbank

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Natural and semi-synthetic compounds are being studied as novel phosphodiesterase 5 (PDE5) inhibitors for the treatment of erectile dysfunction, pulmonary hypertension, and lower urinary symptoms. Maclura pomifera is a source of flavonoids, one of the main classes of molecules investigated for these purposes. The extraction of the natural isoflavone osajin and its modification to obtain a semi-synthetic derivative are described in this short note. 1 H and 13 C-nuclear magnetic resonance spectroscopy (NMR), mass spectrometry, high-performance liquid chromatography (HPLC) and spectroscopic characterization of the title compound are also hereby provided. Two-dimensional (2D) nuclear Overhauser effect spectroscopy (NOESY) NMR, supported by in silico conformational studies, was used to achieve a complete assignment of the proton signals, assessing the correct chemical structure of the compound. Heteronuclear single quantum coherence spectroscopy (HSQC) and heteronuclear multiple bond correlation (HMBC) NMR experiments were performed to assign 13 C chemical shifts. Calculated chemical properties and preliminary in silico docking suggest that this molecule might be a promising candidate as PDE5 inhibitor.

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Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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5-Hydroxy-3-(4-hydroxyphenyl)-8,8-dimethyl-6-(3-methylbut-2-enyl)pyrano[2,3-h]chromen-4-one

Ribaudo

Ongaro

Zagotto

2018

Molbank

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“…A selective α 1A ‐adrenoceptor antagonist, silodosin, has been widely prescribed for patients with BPH/LUTS, as it suppresses the resistance to urine flow in the proximal urethra . Recently, tadalafil, a PDE5 inhibitor, also has been used for the treatment of BPH/LUTS . The PDE5 inhibitors suppress the PDE5 enzymes in the lower urinary tract, thereby, relaxing the urethral smooth muscle and ameliorating the lower urinary tract obstruction, and are also reported to improve bladder ischemia, and suppress afferent nerve activity, collagen synthesis and fibrosis .…”

Section: Introductionmentioning

confidence: 99%

“…5 The PDE5 inhibitors suppress the PDE5 enzymes in the lower urinary tract, thereby, relaxing the urethral smooth muscle and ameliorating the lower urinary tract obstruction, 5 and are also reported to improve bladder ischemia, and suppress afferent nerve activity, collagen synthesis and fibrosis. 5,6 Furthermore, clinical data showed that silodosin and tadalafil have a protective effect on voiding symptoms and storage symptoms in male patients with BPH/LUTS. 5,7 Vascular risk factors, such as hypertension and hyperlipidemia, are involved in the development of bladder overactivity.…”

mentioning

confidence: 99%

Effects of silodosin and tadalafil on bladder dysfunction in spontaneously hypertensive rats: Possible role of bladder blood flow

et al. 2020

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Objectives To investigate the effects of an alpha1‐adrenoceptor antagonist, silodosin, or a phosphodiesterase type 5 inhibitor, tadalafil, on bladder overactivity in spontaneously hypertensive rats. Methods Twelve‐week‐old male spontaneously hypertensive rats were perorally administered silodosin (100 µg/kg), tadalafil (2 or 10 mg/kg) or vehicle once daily for 6 weeks. Wistar rats were used as normotensive controls and were treated with the vehicle. At 18‐weeks‐old, the effects of silodosin or tadalafil on blood pressure, bladder blood flow, urodynamic parameters (i.e. micturition frequency, urine output, inter‐contraction interval, maximum voiding pressure, single voided volume and post‐voiding residual urine volume), and bladder tissue levels of malondialdehyde, interleukin‐6 and tumor necrosis factor‐alpha were measured. Results A significant increase in blood pressure, micturition frequency and bladder tissue levels of malondialdehyde, interleukin‐6 and tumor necrosis factor‐alpha was noted in spontaneously hypertensive rats. The single voided volume, bladder capacity and bladder blood flow were significantly lower in the spontaneously hypertensive rats than in the Wistar rats. Treatment with silodosin and the higher dose of tadalafil improved the urodynamic parameters, bladder blood flow and bladder tissue levels of malondialdehyde in the spontaneously hypertensive rats without affecting the blood pressure and bladder tissue levels of interleukin‐6 and tumor necrosis factor‐alpha. Conclusions Treatment with silodosin or tadalafil might improve hypertension‐related bladder overactivity, as shown in spontaneously hypertensive rats through an improvement in the bladder blood flow and bladder tissue levels of oxidative stress.

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Nitrogen Monoxide (Nitric Oxide): Bioinorganic Chemistry

Fricker¹

2019

Encyclopedia of Inorganic and Bioinorganic Chemistry

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The discovery of nitrogen monoxide (nitric oxide, NO) as the vasodilator molecule endothelium‐derived relaxing factor revealed a major physiological role for this simple diatomic molecule. We now know that NO regulates cardiovascular function, is a neurotransmitter, and is a component of the innate immune response to infection and cancer. The physiological effects of NO are mediated by its varied chemistry which includes redox chemistry and interaction with transition metals. NO can interact with iron‐heme‐containing proteins including hemoglobin and cytochrome c oxidase, and nonheme iron proteins such as aconitase and bacterial transcription regulatory proteins. NO reacts with superoxide to form the highly reactive peroxynitrite which decomposes to give the hydroxyl radical. Nitrosothiols, thiol adducts of NO, act to control NO release, and to shuttle NO between proteins and transport NO across cell membranes. NO is produced by one of three nitric oxide synthase (NOS) enzymes, endothelial NOS, neuronal NOS, and inducible NOS. Signaling functions are mediated via interaction with the heme‐containing protein soluble guanylate cyclase (GC), which produces the cell signaling molecule cyclic guanosine monophosphate (cGMP). This, in turn, is hydrolyzed by phosphodiesterase 5 (PDE5), which turns off NO signaling. Perturbation in NO function contributes to the pathophysiology of many disease states. Endothelial dysfunction and subsequent reduced NO production contribute to hypertension and atherosclerosis. Excess NO is a mediator of inflammatory disease, and neurodegenerative disease, due in part to the production of peroxynitrite. The cardiovascular collapse observed in septic shock is caused by the vasodilator action of NO. Targeting the NO pathway theoretically provides many opportunities for therapeutic intervention. The NO donor drugs glyceryl trinitrate, isosorbide mononitrate, isosorbide dinitrate, and amyl nitrate are used to treat acute angina; and inhaled NO is used to treat persistent pulmonary hypertension in new born infants. Conversely, NOS inhibitors and NO scavengers have been explored to counteract NO as a mediator of disease. Though promising results have been obtained in animal models of disease these latter approaches have had little clinical success. However, targeting downstream of NO has been more successful with new clinically approved classes of drugs such as the inhibitors of PDE5 sildenafil, tadalafil, and vardenafil; and the stimulator of the NO receptor soluble GC, riociguat. It has become apparent that the biological actions, and biological chemistry, of NO are very complex. New opportunities for drug discovery could result from an improved understanding of the biology of NO.

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PDE5 inhibitors – pharmacology and clinical applications 20 years after sildenafil discovery

Cited by 361 publications

References 77 publications

5-Hydroxy-3-(4-hydroxyphenyl)-8,8-dimethyl-6-(3-methylbut-2-enyl)pyrano[2,3-h]chromen-4-one

5-Hydroxy-3-(4-hydroxyphenyl)-8,8-dimethyl-6-(3-methylbut-2-enyl)pyrano[2,3-h]chromen-4-one

Effects of silodosin and tadalafil on bladder dysfunction in spontaneously hypertensive rats: Possible role of bladder blood flow

Nitrogen Monoxide (Nitric Oxide): Bioinorganic Chemistry

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