Identification of biaryl sulfone derivatives as antagonists of the histamine H3 receptor: Discovery of (R)-1-(2-(4&; prime; -(3-methoxypropylsulfonyl)biphenyl-4-yl)e thyl)-2-methylpyrrolidine (APD916)

The design of a new clinical candidate histamine-H3 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...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (1), p.71-75
Main Authors: Semple, Graeme, Santora, Vincent J, Smith, Jeffrey M, Covel, Jonathan A, Hayashi, Rena, Gallardo, Charlemagne, Ibarra, Jason B, Schultz, Jeffrey A, Park, Douglas M, Estrada, Scott A, Hofilena, Brian J, Smith, Brian M, Ren, Albert, Suarez, Marissa, Frazer, John, Edwards, Jeffrey E, Hart, Ryan, Hauser, Erin K, Lorea, Jodie, Grottick, Andrew J
Format: Article
Language:English
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Summary:The design of a new clinical candidate histamine-H3 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.
ISSN:0960-894X
DOI:10.1016/j.bmcl.2011.11.075