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Discovery of 1-(phenylsulfonyl)-1H-indole-based multifunctional ligands targeting cholinesterases and 5-HT6 receptor with anti-aggregation properties against amyloid-beta and tau
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2021-08-19 , DOI: 10.1016/j.ejmech.2021.113783
Tomasz Wichur 1 , Anna Pasieka 1 , Justyna Godyń 1 , Dawid Panek 1 , Izabella Góral 1 , Gniewomir Latacz 1 , Ewelina Honkisz-Orzechowska 1 , Adam Bucki 1 , Agata Siwek 1 , Monika Głuch-Lutwin 1 , Damijan Knez 2 , Xavier Brazzolotto 3 , Stanislav Gobec 2 , Marcin Kołaczkowski 1 , Raimon Sabate 4 , Barbara Malawska 1 , Anna Więckowska 1
Affiliation  

Multifunctional ligands as an essential variant of polypharmacology are promising candidates for the treatment of multi-factorial diseases like Alzheimer's disease. Based on clinical evidence and following the paradigm of multifunctional ligands we have rationally designed and synthesized a series of compounds targeting processes involved in the development of the disease. The biological evaluation led to the discovery of two compounds with favorable pharmacological characteristics and ADMET profile. Compounds 17 and 35 are 5-HT6R antagonists (Ki = 13 nM and Ki = 15 nM respectively) and cholinesterase inhibitors with distinct mechanisms of enzyme inhibition. Compound 17, a tacrine derivative is a reversible inhibitor of acetyl- and butyrylcholinesterase (IC50 = 8 nM and IC50 = 24 nM respectively), while compound 35 with rivastigmine-derived phenyl N-ethyl-N-methylcarbamate fragment is a selective, pseudo-irreversible inhibitor of butyrylcholinesterase (IC50 = 455 nM). Both compounds inhibit aggregation of amyloid β in vitro (75% for compound 17 and 68% for 35 at 10 μM) moreover, compound 35 is a potent tau aggregation inhibitor in cellulo (79%). In ADMET in vitro studies both compounds showed acceptable metabolic stability on mouse liver microsomes (28% and 60% for compound 17 and 35 respectively), no or little effect on CYP3A4 and 2D6 up to a concentration of 10 μM and lack of toxicity on HepG2 cell line (IC50 values of 80 and 21 μM, for 17 and 35 respectively). Based on the pharmacological characteristics and favorable pharmacokinetic properties, we propose compounds 17 and 35 as an excellent starting point for further optimization and in-depth biological studies.



中文翻译:

发现基于 1-(苯磺酰基)-1H-吲哚的多功能配体靶向胆碱酯酶和 5-HT6 受体,具有抗淀粉样蛋白-β 和 tau 的抗聚集特性

多功能配体作为多药理学的重要变体,是治疗阿尔茨海默病等多因素疾病的有希望的候选者。基于临床证据,并遵循多功能配体的范式,我们合理设计并合成了一系列靶向疾病发展过程的化合物。生物学评估导致发现了两种具有良好药理特性和 ADMET 特征的化合物。化合物1735是 5-HT 6 R 拮抗剂(分别为K i  = 13 nM 和K i  = 15 nM)和具有不同酶抑制机制的胆碱酯酶抑制剂。化合物17,他克林衍生物是乙酰胆碱酯酶和丁酰胆碱酯酶的可逆抑制剂(IC 50  = 8 nM 和 IC 50  = 24 nM),而化合物35与卡巴拉汀衍生的N-乙基-N-甲基氨基甲酸苯酯片段是选择性的假丁酰胆碱酯酶的不可逆抑制剂 (IC 50  = 455 nM)。两种化合物在体外抑制淀粉样蛋白 β 的聚集(化合物17为 75%, 35 在 10 μM 时为 68% )此外,化合物35在纤维素中是一种有效的 tau 聚集抑制剂(79%)。在体外ADMET研究表明,这两种化合物对小鼠肝微粒体的代谢稳定性可接受(化合物1735分别为 28% 和 60%),对 CYP3A4 和 2D6 没有影响或影响很小,浓度高达 10 μM,对 HepG2 细胞系没有毒性(IC 80 和 21 μM 的50 个值,分别为1735)。基于药理特性和良好的药代动力学特性,我们提出化合物1735作为进一步优化和深入生物学研究的绝佳起点。

更新日期:2021-08-29
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