دورية أكاديمية
Design of novel β-carboline derivatives with pendant 5-bromothienyl and their evaluation as phosphodiesterase-5 inhibitors.
| العنوان: | Design of novel β-carboline derivatives with pendant 5-bromothienyl and their evaluation as phosphodiesterase-5 inhibitors. |
|---|---|
| المؤلفون: | El-Gamil DS; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt., Ahmed NS, Gary BD, Piazza GA, Engel M, Hartmann RW, Abadi AH |
| المصدر: | Archiv der Pharmazie [Arch Pharm (Weinheim)] 2013 Jan; Vol. 346 (1), pp. 23-33. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Wiley-VCH Verlag GmbH & Co. KGaA Country of Publication: Germany NLM ID: 0330167 Publication Model: Print Cited Medium: Internet ISSN: 1521-4184 (Electronic) Linking ISSN: 03656233 NLM ISO Abbreviation: Arch Pharm (Weinheim) Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: <2005->: Weinheim Germany : Wiley-VCH Verlag GmbH & Co. KGaA Original Publication: Weinheim, Verlag Chemie GmbH. |
| مواضيع طبية MeSH: | Carbolines/*pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 5/*drug effects , Phosphodiesterase 5 Inhibitors/*pharmacology, Carbolines/chemical synthesis ; Carbolines/chemistry ; Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism ; Diketopiperazines/chemical synthesis ; Diketopiperazines/chemistry ; Diketopiperazines/pharmacology ; Drug Design ; Humans ; Imidazolidines/chemical synthesis ; Imidazolidines/chemistry ; Imidazolidines/pharmacology ; Inhibitory Concentration 50 ; Molecular Structure ; Phosphodiesterase 5 Inhibitors/chemical synthesis ; Phosphodiesterase 5 Inhibitors/chemistry ; Structure-Activity Relationship |
| مستخلص: | New derivatives with the tetrahydro-β-carboline-imidazolidinedione and tetrahydro-β-carboline-piperazinedione scaffolds and a pendant bromothienyl moiety at C-5/C-6 were synthesized and tested for their ability to inhibit PDE5 in vitro. The following SAR can be concluded: The tetracyclic scaffold is essential for PDE5 inhibition; the ethyl group is the most suitable among the adopted N-substituents on the terminal ring (hydantoin/piperazinedione); the appropriate stereochemistry of C-5/C-6 derived from the aldehyde rather than C-11a/C-12a derived from tryptophan appears crucial for inhibition of PDE5; surprisingly, derivatives with the hydantoin terminal ring are more active than their analogs with the piperazinedione ring; the selectivity versus PDE5 relative to PDE11 with cGMP as a substrate is mainly a function of the substitution and stereochemistry pattern of the external ring, in other words of the interaction with the H-loop residues of the isozymes. Thirteen derivatives showed PDE5 inhibitory activity with IC(50) values in the range of 0.16-5.4 µm. Compound 8 was the most potent PDE5 inhibitor and showed selectivity towards PDE5 versus other PDEs, with a selectivity index of 49 towards PDE5 rather than PDE11 with cGMP as the substrate. (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.) |
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| معلومات مُعتمدة: | R01 CA131378 United States CA NCI NIH HHS; R01 CA148817 United States CA NCI NIH HHS; R01 CA155638 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Carbolines) 0 (Diketopiperazines) 0 (Imidazolidines) 0 (Phosphodiesterase 5 Inhibitors) EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 5) |
| تواريخ الأحداث: | Date Created: 20130112 Date Completed: 20131112 Latest Revision: 20211021 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC4980837 |
| DOI: | 10.1002/ardp.201200334 |
| PMID: | 23307609 |
| قاعدة البيانات: | MEDLINE |
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