Optimizacija analogov 3-(4-fluorofenetil)piperidina kot selektivnih zaviralcev butirilholin esteraze

Bajc, Enia (author), Hrast, Martina (mentor), Knez, Damijan (comentor)

Alzheimerjeva bolezen (AB) je najpogostejša oblika demence, ki prizadene predvsem starejšo populacijo ljudi. Zanjo je značilen progresiven kognitivni upad, patološko pa jo lahko okarakteriziramo z zunajcelično agregacijo amiloida beta, znotrajceličnim kopiče-njem nevrofibrilarnih pentelj sestavljenih iz hiperfosforiliranega tau proteina, oksidativ-nim stresom, porušeno homeostazo kovinskih ionov, vnetjem v centralnem živčnem sistemu ter pomanjkanjem živčnega prenašalca acetilholina (ACh) v možganih. Trenutna terapija je osredotočena predvsem na zaviranje holinesteraz – acetilholin esteraze (AChE) in butirilholin esteraze (BChE), saj kar tri registrirane zdravilne učinkovine za terapijo AB zavirajo eno ali obe holinesterazi, četrta registrirana učinkovina za terapijo AB pa je memantin – blokator NMDA receptorjev V okviru magistrske naloge smo se osredotočili na razvoj zaviralcev humane BChE (hBChE), ki v poznejših fazah AB funkcionalno kompenzira zmanjšano aktivnost in koncentracijo encima AChE. Pri načrtovanju smo izhajali iz spojine vodnice, ki zavira hBChE z IC50 vrednostjo 99,8 ± 8,7 nM. Sintetizirali in biokemijsko smo ovrednotili 12 derivatov 3-(4-fluorofenetil)piperidina, pri čemer smo na mestu 3 piperidina uvajali raz-lične substituente z namenom izboljšati jakost vezave v aktivno mesto hBChE. Kot naj-boljši zaviralec se je izkazala spojina 31 (IC50 = 11,30 ± 2,60 nM), ki ima na benzenovem obroču na mestu 4 metilni substituent, piperidinski obroč in benzen pa sta povezana s cis vinilnim distančnikom. Močnejšo jakost inhibicije kot spojina vodnica so imele tudi spo-jine 33 (IC50 = 66,2 ± 13,0 nM), 34 (IC50 = 27,1 ± 6,9 nM), 36 (IC50 = 57,0 ± 4,1 nM), 37 (IC50 = 37,2 ± 7,5 nM) in 38 (IC50 = 92,1 ± 9,5 nM). Vsem tem spojinam je skupno, da sta piperidinski obroč in benzenov obroč povezana z etilenskim distančnikom ali vinilim fragmentom v cis konformaciji. Spojine imajo tudi ustrezne fizikalno-kemijske lastnosti za prehajanje krvno-možganske pregrade in lahko služijo kot dobro izhodišče za nadalj-nje raziskovanje in optimizacijo selektivnih zaviralcev hBChE.

• Language: Slovenian
• Keywords: Alzheimerjeva bolezen, demenca, butirilholin esteraza, zaviralci
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2020
• PID: 20.500.12556/RUL-122252
• Publication date in RUL: 02.12.2020

Secondary language

• Language: English
• Title: Optimisation of 3-(4-fluorophenethyl)piperidine analogues as selective butyrylcholinesterase inhibitors

Abstract

Alzheimer’s disease (AD) is the most common form of dementia that predominantly affects the elderly. AD is characterized by progressive cognitive decline, which is patho-logically accompanied by the deposition of extracellular beta amyloid plaques, intracellu-lar deposition of neurofibrillary tangles constituted of hyperphosphorylated tau protein, oxidative stress, metal ion dyshomeostasis, neuroinflammation and depletion of neuro-transmitter acetylcholine (ACh) in the brain. Current pharmacotherapy is based on inhibi-tion of both cholinesterases - acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) since three approved drugs inhibit one or both cholinesterases.The forth approved drug is memantine, a NMDA receptor blocker. In this research we focused on the development of novel human BChE (hBChE) inhibitors, which in the later stages of AD compensates for reduced activity and expressi-on of AChE. The design of inhibitors was based on hit compound, which inhibits hBChE in nanomolar range with IC50 value of 99.8 ± 8.7 nM. We synthesized and biochemically evaluated twelve 3-(4-fluorophenethyl)piperidine analogues by changing substituents at the position 3 of piperidine in order to improve binding to the active site of hBChE. The most potent inhibitor turned out to be compound 31 (IC50 = 11.30 ± 2.60 nM) with 4-methy substituent on the benzene and cis vinyl linker between piperidine and benzene. Furthermore, compared to the lead compound (IC50 = 99.8 ± 8.7 nM), five other inhibitors also showed improved hBChE potencies: compounds 33 (IC50 = 66.2 ± 13.0 nM), 34 (IC50 = 27.1 ± 6.9 nM), 36 (IC50 = 57.0 ± 4.1 nM), 37 (IC50 = 37.2 ± 7.5 nM) and 38 (IC50 = 92.1 ± 9.5 nM). All of the compounds share one common structural feature; piperidine ring and benzene are concented by ethylene linker or vinyl in cis conformation. Compounds possess appropriate physicochemical properties for permeation of blood-brain barrier and can thus be used as excellent springboard for further research and optimization of selecti-ve hBChE inhibitors.

• Keywords: Alzheimer’s disease, dementia, butyrylcholinesterase, inhibitors