Modulating the Cyclic Guanosine Monophosphate Substrate Selectivity of the Phosphodiesterase 3 Inhibitors by Pyridine, Pyrido[2,3-d]pyrimidine Derivatives and Their Effects upon the Growth of HT-29 Cancer Cell Line
| Autor: | Gary A. Piazza, Marwa Saeed Hany, Bernard D. Gary, Heather N. Tinsley, Ashraf H. Abadi, Amal Abdel Haleem Eissa, Shimaa Awadain Elsharif |
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| Rok vydání: | 2013 |
| Předmět: |
Formamide
Pyrimidine Pyridines Stereochemistry Phosphodiesterase 3 Phosphodiesterase 3 Inhibitors Article Substrate Specificity Structure-Activity Relationship chemistry.chemical_compound Hydrolysis Catalytic Domain Drug Discovery Pyridine Humans Cyclic GMP Cyclic guanosine monophosphate Cell Proliferation Binding Sites Chemistry General Chemistry General Medicine Cyclic Nucleotide Phosphodiesterases Type 3 Molecular Docking Simulation Pyrimidines Cyclization Amine gas treating Selectivity HT29 Cells Protein Binding |
| Zdroj: | Chemical and Pharmaceutical Bulletin. 61:405-410 |
| ISSN: | 1347-5223 0009-2363 |
| DOI: | 10.1248/cpb.c12-00993 |
| Popis: | Analogues with the scaffolds of 3-cyano-4-alkoxyphenyl-6-bromoaryl-2-pyridone and 2-amino-3-cyano-4-alkoxyphenyl-6-bromoarylpyridine were synthesized. Cyclization of the 2-amino derivatives with formic acid and formamide gave the corresponding pyrido[2,3-d]pyrimidin-4(3H)-one and the pyrido[2,3-d]-pyrimidin-4-amine derivatives, respectively. Active phosphodiesterase 3 (PDE3) inhibitors were identified from each of the four aforementioned scaffolds. This is the first report that pyrido[2,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4-amine derivatives can inhibit PDE3. The analogues with the pyridone and pyrido[2,3-d]pyrimidin-4(3H)-one scaffolds inhibited both cAMP and cyclic guanosine monophosphate (cGMP) hydrolysis by PDE3, while the amine containing scaffolds were more selective for cGMP hydrolysis. This observation may set the base for substrate-selective pharmacological modulation of this important class of drug targets and with less side effects, particularly tachcardia. The dual inhibitors of PDE3 were more potent inhibitor towards the growth of HT-29 cancer cell lines. |
| Databáze: | OpenAIRE |
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