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ID: ALA2440017

Journal: Bioorg Med Chem Lett

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

Authors: Gao Z, Hurst WJ, Czechtizky W, Francon D, Griebel G, Nagorny R, Pichat P, Schwink L, Stengelin S, Hendrix JA, George PG.

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

CiteXplore: 24076172

DOI: 10.1016/j.bmcl.2013.09.006