Abstract
The benzimidazole core of the selective non-brain-penetrating H(1)-antihistamine mizolastine was used to identify a series of brain-penetrating H(1)-antihistamines for the potential treatment of insomnia. Using cassette PK studies, brain-penetrating H(1)-antihistamines were identified and in vivo efficacy was demonstrated in a rat EEG/EMG model. Further optimization focused on strategies to attenuate an identified hERG liability, leading to the discovery of 4i with a promising in vitro profile.
MeSH terms
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Animals
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Benzimidazoles / antagonists & inhibitors*
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Benzimidazoles / chemistry*
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Brain / drug effects*
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Chemistry, Pharmaceutical / methods*
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Drug Design
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ERG1 Potassium Channel
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Electroencephalography / methods
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Electromyography / methods
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Ether-A-Go-Go Potassium Channels / chemistry
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Histamine Antagonists / chemical synthesis*
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Histamine Antagonists / pharmacology*
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Humans
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Models, Chemical
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Rats
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Rats, Sprague-Dawley
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Sleep Initiation and Maintenance Disorders / drug therapy*
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Structure-Activity Relationship
Substances
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Benzimidazoles
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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Histamine Antagonists
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KCNH2 protein, human
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2-aminobenzimidazole