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

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概要

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• 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.

• 公益社団法人 日本薬学会の論文

著者

• Eissa Amal

  Department Of Pharmaceutical Chemistry Faculty Of Pharmacy Cairo University

• Abadi Ashraf

  Department Of Pharmaceutical Chemistry Faculty Of Pharmacy Cairo University

• Piazza Gary

  Mitchell Cancer Institute, University of South Alabama

• Hany Marwa

  Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo

• Elsharif Shimaa

  Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo

• Gary Bernard

  Mitchell Cancer Institute, University of South Alabama

• Tinsley Heather

  University of Montevallo

• Abadi Ashraf

  Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo

関連論文

• Synthesis and Anticonvulsant Activity of Certain Substituted Furochromone, Benzofuran and Flavone Derivatives
• Synthesis of Novel 1,3,4-Trisubstituted Pyrazole Derivatives and Their Evaluation as Antitumor and Antiangiogenic Agents
• 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

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