LGCR SMRPD Chemical Research, Sanofi US, 153-1-122, 153 2nd Ave, Waltham, MA 02451, USA.
Bioorg Med Chem Lett. 2013 Nov 15;23(22):6141-5. doi: 10.1016/j.bmcl.2013.09.006. Epub 2013 Sep 8.
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.
先前的研究表明，化合物 1 对组胺 H3 受体（H3R）具有高亲和力（人源（h-H3R），K(i)=8.6 nM，恒河猴（rh-H3R），K(i)=1.2 nM，大鼠（r-H3R），K(i)=16.5 nM），但对 hERG 通道具有高亲和力。在此，我们通过对先导化合物进行优化，报道了一种新型、强效、高选择性的 H3R 拮抗剂/反向激动剂 5a(SS)（SAR110068）的发现，该化合物具有可接受的 hERG 通道选择性以及理想的药理学和药代动力学特性。通过在大鼠的光照阶段使用 EEG 记录研究 5a(SS) 对睡眠-觉醒周期的显著唤醒作用，支持其在人类睡眠-觉醒障碍中的潜在治疗用途。
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