Abstract
The synthesis and evaluation of a series of 2,4-diaminopyridine-based neuropeptide Y Y1 (NPY Y1) receptor antagonists are described. Compound 1 was previously reported by our laboratory to be a potent and selective Y1 antagonist; however, 1 was also found to have potent hERG inhibitory activity. The main focus of this communication is structure-activity relationship development aimed at eliminating the hERG activity of 1. This resulted in the identification of compound 3d as a potent and selective NPY Y1 antagonist with reduced hERG liability.
MeSH terms
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4-Aminopyridine / analogs & derivatives*
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4-Aminopyridine / chemistry
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Animals
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CHO Cells
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Cell Line
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Chemistry, Pharmaceutical / methods
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Cricetinae
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Cricetulus
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Drug Design
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
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Ether-A-Go-Go Potassium Channels / chemistry
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Humans
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Hydrogen-Ion Concentration
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Inhibitory Concentration 50
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Models, Chemical
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Receptors, Neuropeptide Y / antagonists & inhibitors*
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Receptors, Neuropeptide Y / chemistry
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Recombinant Proteins / chemistry
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Structure-Activity Relationship
Substances
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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KCNH2 protein, human
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Receptors, Neuropeptide Y
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Recombinant Proteins
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neuropeptide Y-Y1 receptor
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2,4-diaminopyridine
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4-Aminopyridine