Adamed Ltd., Pieńków 149, 05-152 Czosnów, Poland.
J Med Chem. 2014 Jun 12;57(11):4543-57. doi: 10.1021/jm401895u. Epub 2014 May 23.
In order to target behavioral and psychological symptoms of dementia (BPSD), we used molecular modeling-assisted design to obtain novel multifunctional arylsulfonamide derivatives that potently antagonize 5-HT(6/7/2A) and D2 receptors, without interacting with M1 receptors and hERG channels. In vitro studies confirmed their antagonism of 5-HT(7/2A) and D2 receptors and weak interactions with key antitargets (M1R and hERG) associated with side effects. Marked 5-HT6 receptor affinities were also observed, notably for 6-fluoro-3-(piperidin-4-yl)-1,2-benzoxazole derivatives connected by a 3-4 unit alkyl linker with mono- or bicyclic, lipophilic arylsulfonamide moieties. N-[4-[4-(6-Fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]butyl]benzothiophene-2-sulfonamide (72) was characterized in vitro on 14 targets and antitargets. It displayed dual blockade of 5-HT6 and D2 receptors and negligible interactions at hERG and M1 receptors. Unlike reference antipsychotics, 72 displayed marked antipsychotic and antidepressant activity in rats after oral administration, in the absence of cognitive or motor impairment. This profile is particularly attractive when targeting a fragile, elderly BPSD patient population.
为了靶向痴呆的行为和心理症状(BPSD),我们使用分子建模辅助设计获得了新型多功能芳基磺酰胺衍生物,它们能够强力拮抗 5-HT(6/7/2A)和 D2 受体,而不与 M1 受体和 hERG 通道相互作用。体外研究证实了它们对 5-HT(7/2A)和 D2 受体的拮抗作用,以及与副作用相关的关键靶标(M1R 和 hERG)的弱相互作用。还观察到显著的 5-HT6 受体亲和力,特别是对于通过 3-4 个单元烷基 linker 连接的具有单环或双环脂溶性芳基磺酰胺部分的 6-氟-3-(哌啶-4-基)-1,2-苯并恶唑衍生物。N-[4-[4-(6-氟-1,2-苯并恶唑-3-基)哌啶-1-基]丁基]苯并噻吩-2-磺酰胺(72)在体外对 14 个靶标和抗靶标进行了表征。它显示出对 5-HT6 和 D2 受体的双重阻断作用,并且与 hERG 和 M1 受体的相互作用可以忽略不计。与参考抗精神病药不同,72 在口服给药后在大鼠中显示出明显的抗精神病和抗抑郁活性,而没有认知或运动障碍。当靶向脆弱的老年 BPSD 患者人群时,这种特征尤其具有吸引力。