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Multifunctional 6-fluoro-3-[3-(pyrrolidin-1-yl)propyl]-1,2-benzoxazoles targeting behavioral and psychological symptoms of dementia (BPSD).
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-02-18 , DOI: 10.1016/j.ejmech.2020.112149
Adam Bucki 1 , Monika Marcinkowska 1 , Joanna Śniecikowska 1 , Agnieszka Zagórska 2 , Marek Jamrozik 2 , Maciej Pawłowski 2 , Monika Głuch-Lutwin 2 , Agata Siwek 2 , Magdalena Jakubczyk 2 , Karolina Pytka 2 , Magdalena Jastrzębska-Więsek 2 , Anna Partyka 2 , Anna Wesołowska 2 , Paweł Mierzejewski 3 , Marcin Kołaczkowski 1
Affiliation  

Patients suffering from dementia experience cognitive deficits and 90% of them show non-cognitive behavioral and psychological symptoms of dementia (BPSD). The spectrum of BPSD includes agitation, depression, anxiety and psychosis. Antipsychotics, e.g. quetiapine, have been commonly used off-label to control the burdensome symptoms, though they cause serious side effects and further cognitive impairment. Therefore, the development of targeted therapy for BPSD, suitable for elderly patients, remains relevant. A multitarget-directed ligand, acting on serotonin 5-HT2A and dopamine D2 receptors (R) and thus exerting anti-aggressive and antipsychotic activity, as well as on 5-HT6Rs and 5-HT7Rs (potential pro-cognitive, antidepressant and anxiolytic activity), poses a promising strategy for the treatment of BPSD. Antitargeting muscarinic M3R and hERG channel is expected to reduce the risk of side effects. We obtained a series of stereoisomeric compounds by combining 6-fluoro-1,2-benzoxazole moiety and arylsulfonamide fragment through pyrrolidin-1-yl-propyl linker. N-[(3R)-1-[3-(6-fluoro-1,2-benzoxazol-3-yl)propyl]pyrrolidin-3-yl]-1-benzothiophene-2-sulfonamide showed a substantial affinity for the targets of interest (pKi = 8.32-9.35) and no significant interaction with the antitargets. Functional studies revealed its antagonist efficacy (pKB = 7.41-9.03). The lead compound showed a promising profile of antipsychotic-like activity in amphetamine- and MK-801-induced hyperlocomotion (MED = 2.5 mg/kg), antidepressant-like, as well as anxiolytic-like activity in mice (MED = 0.312 and 1.25 mg/kg in the forced swim and four-plate tests, respectively). Notably, the novel compound didn't affect spontaneous locomotor activity, nor induced catalepsy or memory deficits (step-through passive avoidance test) in therapeutically relevant doses, which proved its benign safety profile. The overall pharmacological characteristics of the lead compound outperformed the reference drug quetiapine, making it a promising option for evaluation in the treatment of BPSD.

中文翻译:

针对痴呆症的行为和心理症状的多功能6-氟-3- [3-(吡咯烷-1-基)丙基] -1,2-苯并恶唑。

患有痴呆症的患者会出现认知功能障碍,其中90%的人表现出痴呆症的非认知行为和心理症状(BPSD)。BPSD的范围包括躁动,抑郁,焦虑和精神病。抗精神病药,例如喹硫平,尽管会引起严重的副作用和进一步的认知障碍,但通常已在标签外使用以控制沉重的症状。因此,开发适用于老年患者的BPSD靶向治疗仍然有意义。一种多靶标配体,可作用于5-羟色胺5-HT2A和多巴胺D2受体(R),从而发挥抗侵略和抗精神病活性,并具有5​​-HT6R和5-HT7R(潜在的前认知,抗抑郁和抗焦虑活性) ),为BPSD的治疗提出了有希望的策略。抗靶向毒蕈碱M3R和hERG通道有望降低副作用的风险。我们通过吡咯烷基-1-基-丙基连接基结合6-氟-1,2-苯并恶唑基团和芳基磺酰胺片段,获得了一系列立体异构化合物。N-[(3R)-1- [3-(6-氟-1,2-苯并恶唑-3-基)丙基]吡咯烷-3-基] -1-苯并噻吩-2-磺酰胺显示对靶标的亲和力(pKi = 8.32-9.35),并且与抗靶标没有明显的相互作用。功能研究显示其拮抗剂功效(pKB = 7.41-9.03)。该先导化合物在苯丙胺和MK-801引起的运动过度(MED = 2.5 mg / kg),抗抑郁药样以及抗焦虑药样小鼠中表现出抗精神病样活性的前景(MED = 0.312和1.25 mg / kg分别在强制游泳和四板试验中)。值得注意的是 该新化合物在治疗相关剂量下不会影响自发运动能力,也不会引起僵直或记忆缺陷(逐步被动回避测试),证明了其良性安全性。铅化合物的整体药理特性优于参考药物喹硫平,使其成为评估BPSD治疗的有前途的选择。
更新日期:2020-02-20
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