Pseudosaccharin amines as potent and selective KV1.5 blockers

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 21; pp. 4983 - 4986
• Main Authors: Lloyd, John, Finlay, Heather J., Kover, Alexander, Johnson, James, Pi, Zulan, Jiang, Ji, Neels, James, Cavallaro, Cullen, Wexler, Ruth, Conder, Mary Lee, Shi, Hong, Li, Danshi, Sun, Huabin, Chimalakonda, Anjaneya, Huang, Christine, Salvati, Mark, Levesque, Paul
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2015
• Subjects: AERP; Amines - chemical synthesis; Amines - chemistry; Amines - pharmacology; Animals; Atrial fibrillation; Blood Pressure - drug effects; Cyclohexanes - chemistry; Cyclohexanes - pharmacology; Dose-Response Relationship, Drug; Humans; IKur; KV1.5; Kv1.5 Potassium Channel - antagonists & inhibitors; Kv1.5 Potassium Channel - metabolism; Mice; Molecular Structure; Phenethylamine; Potassium Channel Blockers - chemical synthesis; Potassium Channel Blockers - chemistry; Potassium Channel Blockers - pharmacology; Rabbits; Rats; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Structure-Activity Relationship; Phenethylamine; AERP; KV1.5; IKur; Atrial fibrillation; I(Kur); K(V)1.5
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.02.066

Synthesis of pseudosaccharin amines as KV1.5 blockers led to the discovery of potent antagonists such as 17d. These compounds had potent pharmacodynamic activity, however, showed off-target activities such as hemodynamic effects. [Display omitted] Phenethyl aminoheterocycles like compound 1 were known to be potent IKur 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 KV1.5 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.