Discovery of a potent, selective, and orally bioavailable histamine H3 receptor antagonist SAR110068 for the treatment of sleepawake disorders

Previous studies have shown that compound 1 displayed high affinity towards histamine H3 receptor (H3R), (human (h-H3R), Ki = 8.6 nM, rhesus monkey (rh-H3R), Ki = 1.2 nM, and rat (r-H3R), Ki = 16.5 nM), but exhibited high affinity for hERG channel. Herein, we report the discovery of a novel, potent,...

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Published inBioorganic & medicinal chemistry letters Vol. 23; no. 22; pp. 6141 - 6145
Main Authors Gao, Zhongli, Hurst, William, Czechtizky, Werngard, Francon, Dominique, Griebel, Guy, Nagorny, Raisa, Pichat, Philippe, Schwink, Lothar, Stengelin, Siegfried, Hendrix, James, George, Pascal
Format Journal Article
LanguageEnglish
Published 01.11.2013
Subjects
EEG
Macaca mulatta
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Summary:Previous studies have shown that compound 1 displayed high affinity towards histamine H3 receptor (H3R), (human (h-H3R), Ki = 8.6 nM, rhesus monkey (rh-H3R), Ki = 1.2 nM, and rat (r-H3R), Ki = 16.5 nM), but exhibited high affinity for hERG channel. Herein, we report the discovery of a novel, potent, and highly selective H3R antagonist/inverse agonist 5a(SS) (SAR110068) with acceptable hERG channel selectivity and desirable pharmacological and pharmacokinetic properties through lead optimization sequence. The significant awakening effects of 5a(SS) on sleepawake cycles studied by using EEG recording in rats during their light phase support its potential therapeutic utility in human sleepawake disorders.
Bibliography:ObjectType-Article-2
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ISSN:0960-894X
DOI:10.1016/j.bmcl.2013.09.006