Design, Synthesis, and Biological Evaluation of AT1 Angiotensin II Receptor Antagonists Based on the Pyrazolo[3,4-b]pyridine and Related Heteroaromatic Bicyclic Systems

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• 作者：Andrea Cappelli ; Chiara Nannicini ; Andrea Gallelli ; Germano Giuliani ; Salvatore Valenti ; Gal.la Pericot Mohr ; Maurizio Anzini ; Laura Mennuni ; Flora Ferrari ; Gianfranco Caselli ; Antonio Giordani ; Walte
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：April 10, 2008
• 年：2008
• 卷：51
• 期：7
• 页码：2137 - 2146
• 全文大小：785K
• 年卷期：v.51,no.7(April 10, 2008)
• ISSN：1520-4804

文摘

Novel AT₁ receptor antagonists bearing the pyrazolo[3,4-b]pyridine bicyclic heteroaromatic system (or structurally related moieties) were designed and synthesized as the final step of a large program devoted to the development of new antihypertensive agents and to the understanding of the molecular basis of their pharmacodynamic and pharmacokinetic properties. The preliminary pharmacological characterization revealed nanomolar AT₁ receptor affinity for several compounds of the series and a potent antagonistic activity in isolated rabbit aortic strip functional assay for 7c and 8a. These results stimulated the study of the biopharmaceutical properties of some selected compounds, which were found to be characterized by a permeability from medium to high. Remarkably, the least permeable 7c showed both permeability and oral bioavailability (80%) higher than losartan, but its terminal half-life was shorter. These results suggest that the permeability is not a limiting factor in the pharmacokinetics of these AT₁ receptor antagonists.