High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodiesterase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patients

Weeks, James L.; Zoraghi, Roya; Beasley, Alfreda; Sekhar, Konjeti R.; Francis, Sharron H.; Corbin, Jackie D.

doi:10.1038/sj.ijir.3901283

Cited by 64 publications

(55 citation statements)

References 20 publications

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“…However, there is a cost to this treatment. The side effects of sildenafil citrate and tadalafil, owing to inhibiting PDE6 and 11, may cause headache and optical interruption [4][5][6] . Nevertheless, certain components from natural herbs and products from Traditional Chinese Medicines (TCM) can treat erectile dysfunction [7,8] .…”

Section: Introductionmentioning

confidence: 99%

Discovery of potent inhibitors for phosphodiesterase 5 by virtual screening and pharmacophore analysis

et al. 2009

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Aim: To explore the potent inhibitor from one of the Traditional Chinese medicine (TCM), Epimedium sagittatum. Methods: We predicted the potent compound, eS03b, de novo evolution from the four Epimedium sagittatum components were verified by molecular docking, pharmacophore analysis, and analysis of quantitative structure-activity relationship (QSAR) model, which was constructed by multiple linear regression. Results: ES03b was chosen to undergo drug modification via de novo evolution. By analyzing the pharmacophore features, we found that the hydrophobic core in the binding site and the hydrogen bond generated at Asn663 played key roles in designing PDE5 inhibitors. eS03b generated 49 diversities (evo01-49). evo48 had high activity in prediction. Although the value of prediction was overestimated, evo48 was suggested as the potent lead. Conclusion: In this study, we showed that the hydrophobic core in the binding site and hydrogen bond production on Asn663 played key roles to design PDE5 inhibitors. From several require validation analysis, Evo48 was suggested to be a potent inhibitor.

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Section: Introductionmentioning

confidence: 99%

Discovery of potent inhibitors for phosphodiesterase 5 by virtual screening and pharmacophore analysis

et al. 2009

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“…Bu bileşikler ayrıca PDE11 ile de etkileşirler. 160 Sildenafil, nöron uyarmak ve sıçanda inme sonrası fonksiyonel iyileşmeyi teşvik etmek için kullanılmıştır. 79,80 Sıçanda hipoksinin neden olduğu akciğer hipertansiyonunda etkili olduğu ve sigara içenlerde endotel bağımlı vazodilatasyonu geliştir-diği saptanmıştır.…”

Section: Pde7bunclassified

Phosphodiesterase Enzymes and Inhibitors: Review

Tuğrak¹,

Küçükoğlu²

2016

Turkiye Klinikleri J Pharm Sci

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Ö ÖZ ZE ET T Siklik nükleotid fosfodiesteraz enzimleri, vücutta her dokuda ve hücrede bulunabilen enzimlerdir. cAMP ve cGMP'yi hidroliz ettikleri için hücre sinyallerinde önemli rol oynarlar. PDE süper ailesi PDE1-PDE11 arasında olmak üzere 11 tanedir. Memeli hücrelerinde her bir aile 20'den fazla gen vermek için birdört farklı gen taşımaktadır. Bu genler 50'den fazla farklı PDE proteinini kodlarlar. PDE enzimleri içerisinde özellikle PDE1 ve PDE6 iyi karakterize edilmiş izozimlerdir. PDE'ler hücre ve dokularda spesifik dağılım gösteren enzimlerdir. Vücudun farklı doku ve organlarında bulunan PDE enzimleri farklılık gösterir. Bu sayede çeşitli hücre fonksiyonlarında farklı fizyolojik olaylara aracılık edebilirler. PDE izoenzimlerinin hücre ve doku fonksiyonlarına özel katkıları ve patofizyolojik düzenlenmeleri bugün önemli bir araştırma alanı oluşturmaktadır. Bu durum, etkileri henüz tam olarak belirlenmediği için özellikle PDE7-PDE11 gibi yeni PDE ailelerini daha çok ilgilendirmektedir. İnflamasyon, nörodejenerasyon ve kanser gibi birçok patolojik durumda meydana gelen değişiklikler, hücre içi sinyallerle ilgili PDE'lerin serbestleşmesini, bu patolojilerin önlenmesini, ayrıca bu tür patolojik durumların tedavisinde gözlemle-nen zorlukları açıklayabilir. Bu konularda yapılacak araştırmalar sonucu elde edilecek bulgular henüz kesin tedavisi bulunmayan hastalıkların tedavisinde yeni gelişmelere yol açabilir. Bu çalışmada, PDE enzimlerinin özellikleri, vücutta bulundukları doku ve organlar ile patofizyolojik olaylardaki rolleri açık-lanmış, ilaveten PDE inhibitörü ilaçlar anlatılmıştır. Ayrıca yeni geliştirilen ve ruhsatlandırma çalışmaları devam eden PDE inhibitörü bileşikler hakkında da bilgi verilmiştir.A An na ah ht ta ar r K Ke el li im me el le er r: : Fosfodiesteraz inhibitörleri; 2',3'-siklik AMP; 2',3'-siklik GMP A AB BS ST TR RA AC CT T Cyclic nucleotide phosphodiesterase enzymes can be found in every tissue and cell in the body. They play an important role in cell signaling because they hydrolyze cAMP and cGMP. PDE superfamily is 11 units, including PDE1-PDE11. Each family in mammalian cells encompasses 1 to 4 distinct genes, to give more than 20 genes. These genes encode more than 50 different PDE proteins. PDE enzymes in particular PDE1 and PDE6 are isozymes have been well characterized. PDEs are enzymes exhibiting specific distribution in cells and tissues. PDE enzymes located in different tissues and organs of the body vary. In this way, they can mediate different physiological events in various cell functions. Today, private contributions and pathophysiological regulations of PDE isoenzymes in cell and tissue functions constitute an important research field. This situation is more relevant for especially new PDE families such as PDE7-PDE11, because their effects have not been fully determined. Changes that occurs in many pathological situations such as inflammation, neurodegeneration and cancer, may explain the liberalization of PDEs related to the intracellular signaling as well as prevention of th...

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“…13 The PDE5A1/PDE11A4 selectivities for sildenafil, vardenafil and tadalafil are 1000-, 9300-and 40-fold, and this suggests that these PDE inhibitors are unlikely to inhibit PDE11A4 in patients with ED. 14 In addition to half-lives, dissociation rates from binding sites are determinants of the duration of action of drugs with slow dissociation prolonging duration of action. The ability of the 3 H-form of the PDE5 inhibitors to dissociate from the enzyme has been measured.…”

Section: Molecular Pharmacologymentioning

confidence: 99%

Do vardenafil and tadalafil have advantages over sildenafil in the treatment of erectile dysfunction?

Doggrell

2006

Int J Impot Res

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Erectile dysfunction (ED) affects up to 50% of men between the ages of 40 and 70 years of age. Sildenafil, vardenafil and tadalafil have all been shown to be similarly effective in the treatment of men with ED of vary etiologies, to have similar adverse effects profiles, and to improve quality-oflife by similar amounts. As these phosphodiesterase 5 (PDE5) inhibitors all increase the hypotensive effects of nitrates, they are not suitable for use in patients taking nitrates for the treatment of ischaemic heart disease. All three inhibitors must be used with caution in patients taking a 1 -adrenoceptors antagonists for benign prostatic hyperplasia. Although nonarteritic anterior ischaemic neuropathy has been reported in some users of the PDE5 inhibitors, there is no conclusive evidence that PDE5 inhibitors cause this rare effect. Tadalafil has a longer half-life than sildenafil or vardenafil, and a longer duration of action than sildenafil and vardenafil. Most preference studies have shown tadalafil to be preferred, but there are serious limitations to some of these studies. One approach to treatment is to give each patient a short-and long-acting agent, and for individuals to decide their preference.

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High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodiesterase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patients

Cited by 64 publications

References 20 publications

Discovery of potent inhibitors for phosphodiesterase 5 by virtual screening and pharmacophore analysis

Discovery of potent inhibitors for phosphodiesterase 5 by virtual screening and pharmacophore analysis

Phosphodiesterase Enzymes and Inhibitors: Review

Do vardenafil and tadalafil have advantages over sildenafil in the treatment of erectile dysfunction?

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