Abstract
The design of a new clinical candidate histamine-H(3) receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by replacement of the sulfonamide linkage with a sulfone. One compound from this series, 2j (APD916) increased wakefulness in rodents as measured by polysomnography with a duration of effect consistent with its pharmacokinetic properties. The identification of a suitable salt form of 2j allowed it to be selected for further development.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Area Under Curve
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Biphenyl Compounds / chemistry*
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Biphenyl Compounds / pharmacology*
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Brain / metabolism
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Central Nervous System / 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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Ether-A-Go-Go Potassium Channels / chemistry
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Histamine Antagonists / chemistry*
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Histamine Antagonists / pharmacokinetics
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Humans
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Inhibitory Concentration 50
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Mice
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Models, Chemical
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Pyrrolidines / antagonists & inhibitors
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Pyrrolidines / chemistry*
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Pyrrolidines / pharmacology*
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Rats
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Receptors, Histamine H3 / chemistry*
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Sleep / drug effects
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Sulfones / chemistry*
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Temperature
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Wakefulness / drug effects
Substances
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(R)-1-(2-(4'-(3-methoxypropylsulfonyl)biphenyl-4-yl)ethyl)-2-methylpyrrolidine
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Biphenyl Compounds
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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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Pyrrolidines
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Receptors, Histamine H3
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Sulfones
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pyrrolidine