ArticleBiochemical pharmacology2008
An insight into the pharmacophores of phosphodiesterase-5 inhibitors from synthetic and crystal structural studies.
Article in Biochemical pharmacology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 30 citations in OpenAlex.
- Discovery of Indole-Based PDE5 Inhibitors: Synthesis and Pharmacological Evaluation.ACS medicinal chemistry letters · 2025Article
- Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission.Science advances · 2024Article
- Investigation of PDE5/PDE6 and PDE5/PDE11 selective potent tadalafil-like PDE5 inhibitors using combination of molecular modeling approaches, molecular fingerprint-based virtual screening protocols and structure-based pharmacophore development.Journal of enzyme inhibition and medicinal chemistry · 2017Article
- Utilization of protein intrinsic disorder knowledge in structural proteomics.Biochimica et biophysica acta · 2013Article
- Identification of amino acid residues responsible for the selectivity of tadalafil binding to two closely related phosphodiesterases, PDE5 and PDE6.The Journal of biological chemistry · 2012Article
- Exploring the PDE5 H-pocket by ensemble docking and structure-based design and synthesis of novel β-carboline derivatives.European journal of medicinal chemistry · 2012Article
- Combining 2D and 3D in silico methods for rapid selection of potential PDE5 inhibitors from multimillion compounds' repositories: biological evaluation.Molecular diversity · 2012Article
- A p-methoxybenzyl (PMB) protection/deprotection approach toward the synthesis of 5-phenoxy-4-chloro-N-(aryl/alkyl) thiophene-2-sulfonamides.Molecular diversity · 2010Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Selective inhibitors of cyclic nucleotide phosphodiesterase-5 (PDE5) have been used as drugs for treatment of male erectile dysfunction and pulmonary hypertension. An insight into the pharmacophores of PDE5 inhibitors is essential for development of second generation of PDE5 inhibitors, but has not been completely illustrated. Here we report the synthesis of a new class of the sildenafil derivatives and a crystal structure of the PDE5 catalytic domain in complex with 5-(2-ethoxy-5-(sulfamoyl)-3-thienyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (12). Inhibitor 12 induces conformational change of the H-loop (residues 660-683), which is different from any of the known PDE5 structures. The pyrazolopyrimidinone groups of 12 and sildenafil are well superimposed, but their sulfonamide groups show a positional difference of as much as 1.5A. The structure-activity analysis suggests that a small hydrophobic pocket and the H-loop of PDE5 are important for the inhibitor affinity, in addition to two common elements for binding of almost all the PDE inhibitors: the stack against the phenylalanine and the hydrogen bond with the invariant glutamine. However, the PDE5-12 structure does not provide a full explanation to affinity changes of the inhibitors. Thus alternatives such as conformational change of the M-loop are open and further structural study is required.
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