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Eur J Med Chem. 2015 May 5;95:349-56. doi: 10.1016/j.ejmech.2015.03.054. Epub 2015 Mar 24.

3,4-Diaza-bicyclo[4.1.0]hept-4-en-2-one phenoxypropylamine analogs of irdabisant (CEP-26401) as potent histamine-3 receptor inverse agonists with robust wake-promoting activity.

Author information

1
Discovery and Product Development, Teva Global R&D., 145 Brandywine Parkway, West Chester, PA 19380, USA. Electronic address: robert.hudkins@tevapharm.com.
2
Discovery and Product Development, Teva Global R&D., 145 Brandywine Parkway, West Chester, PA 19380, USA.

Abstract

A novel series of 3,4-diaza-bicyclo[4.1.0]hept-4-en-2-ones were designed and synthesized as H3R analogs of irdabisant 6. Separation of the isomers, assignment of the stereochemistry by crystallography, and detailed profiling of diastereomers 25 and 26 led to the identification of (1R,6S)-5-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy]phenyl}-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one 25 as a potential second generation H3R candidate. Diastereomer 25 had high H3R binding affinity, excellent selectivity, displayed potent H3R functional antagonism and robust wake-promoting activity in vivo, and showed acceptable pharmacokinetic and pharmaceutical profiles for potential further development.

KEYWORDS:

CEP-26401; H(3) inverse agonist; Histamine H(3) receptor; Irdabisant; Pyridazin-3-one; Sleep-wake

PMID:
25827402
DOI:
10.1016/j.ejmech.2015.03.054
[Indexed for MEDLINE]

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