Optimization of a Tertiary Alcohol Series of Phosphodiesterase-4 (PDE4) Inhibitors: Structure−Activity Relationship Related to PDE4 Inhibition and Human Ether-a-go-go Related Gene Potassium Channel Binding Affinity
| Autor: | Richard W. Friesen, Yves Ducharme, Richard G. Ball, Marc Blouin, Louise Boulet, Bernard Côté, Richard Frenette, Mario Girard, Daniel Guay, Zheng Huang, Thomas R. Jones, France Laliberté, Joseph J. Lynch, Joseph Mancini, Evelyn Martins, Paul Masson, Eric Muise, Douglas J. Pon, Peter K. S. Siegl, Angela Styhler, Nancy N. Tsou, Mervyn J. Turner, Robert N. Young, Yves Girard |
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| Rok vydání: | 2003 |
| Předmět: |
ERG1 Potassium Channel
Potassium Channels Phosphodiesterase Inhibitors Pyridines Vomiting Bronchoconstriction Guinea Pigs hERG In Vitro Techniques Crystallography X-Ray Cyclic N-Oxides Electrocardiography Structure-Activity Relationship Dogs In vivo Drug Discovery Animals Humans Structure–activity relationship Saimiri Sheep biology Voltage-gated ion channel Tumor Necrosis Factor-alpha Chemistry Stereoisomerism Ether-A-Go-Go Potassium Channels Potassium channel Cyclic Nucleotide Phosphodiesterases Type 4 Rats Long QT Syndrome Biochemistry 3' 5'-Cyclic-AMP Phosphodiesterases Potassium Channels Voltage-Gated Enzyme inhibitor Alcohols biology.protein Molecular Medicine Protein Binding Potassium Channel Binding |
| Zdroj: | Journal of Medicinal Chemistry. 46:2413-2426 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A SAR study on the tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors related to 1 is described. In addition to inhibitory potency against PDE4 and the lipopolysaccharide-induced production of TNFalpha in human whole blood, the binding affinity of these compounds for the human ether-a-go-go related gene (hERG) potassium channel (an in vitro measure for the potential to cause QTc prolongation) was assessed. Four key structural moieties in the molecule were studied, and the impact of the resulting modifications in modulating these activities was evaluated. From these studies, (+)-3d (L-869,298) was identified as an optimized structure with respect to PDE4 inhibitory potency, lack of binding affinity to the hERG potassium channel, and pharmacokinetic behavior. (+)-3d exhibited good in vivo efficacy in several models of pulmonary function with a wide therapeutic index with respect to emesis and prolongation of the QTc interval. |
| Databáze: | OpenAIRE |
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