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Optimizacija analogov 3-(4-fluorofenetil)piperidina kot selektivnih zaviralcev butirilholin esteraze
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Bajc, Enia
(
Author
),
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Hrast, Martina
(
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)
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Knez, Damijan
(
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)
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Abstract
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
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1074
Downloads:
197
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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
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