Details

Autor(en) / Beteiligte

• Gao, Zhongli
• Hurst, William J.
• Czechtizky, Werngard
• Francon, Dominique
• Griebel, Guy
• Nagorny, Raisa
• Pichat, Philippe
• Schwink, Lothar
• Stengelin, Siegfried
• Hendrix, James A.
• George, Pascal G.

Titel

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

Ist Teil von

• Bioorganic & medicinal chemistry letters, 2013-11, Vol.23 (22), p.6141-6145

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2013

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Previous studies have shown that compound 1 displayed high affinity towards histamine H3 receptor (H3R), (human (h-H3R), Ki=8.6nM, rhesus monkey (rh-H3R), Ki=1.2nM, and rat (r-H3R), Ki=16.5nM), 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 sleep–wake cycles studied by using EEG recording in rats during their light phase support its potential therapeutic utility in human sleep–wake disorders.