1. Pseudosaccharin amines as potent and selective KV1.5 blockers.
- Author
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Lloyd J, Finlay HJ, Kover A, Johnson J, Pi Z, Jiang J, Neels J, Cavallaro C, Wexler R, Conder ML, Shi H, Li D, Sun H, Chimalakonda A, Huang C, Salvati M, and Levesque P
- Subjects
- Amines chemical synthesis, Amines chemistry, Animals, Blood Pressure drug effects, Cyclohexanes chemistry, Cyclohexanes pharmacology, Dose-Response Relationship, Drug, Humans, Kv1.5 Potassium Channel metabolism, Mice, Molecular Structure, Potassium Channel Blockers chemical synthesis, Potassium Channel Blockers chemistry, Rabbits, Rats, Spiro Compounds chemistry, Spiro Compounds pharmacology, Structure-Activity Relationship, Amines pharmacology, Kv1.5 Potassium Channel antagonists & inhibitors, Potassium Channel Blockers pharmacology
- Abstract
Phenethyl aminoheterocycles like compound 1 were known to be potent I(Kur) blockers although they lacked potency in vivo. Modification of the heterocycle led to the design and synthesis of pseudosaccharin amines. Compounds such as 14, 17d and 21c were found to be potent K(V)1.5 blockers and selective over other cardiac ion channels. These compounds had potent pharmacodynamic activity, however, they also showed off-target activities such as hemodynamic effects., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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