Discovery and Biological Evaluation of a Novel Highly Potent Selective Butyrylcholinsterase Inhibitor.
J Med Chem
; 63(17): 10030-10044, 2020 09 10.
Article
em En
| MEDLINE
| ID: mdl-32787113
ABSTRACT
To discover novel BChE inhibitors, a hierarchical virtual screening protocol followed by biochemical evaluation was applied. The most potent compound 8012-9656 (eqBChE IC50 = 0.18 ± 0.03 µM, hBChE IC50 = 0.32 ± 0.07 µM) was purchased and synthesized. It inhibited BChE in a noncompetitive manner and could occupy the binding pocket forming diverse interactions with the target. 8012-9656 was proven to be safe in vivo and in vitro and showed comparable performance in ameliorating the scopolamine-induced cognition impairment to tacrine. Additionally, treatment with 8012-9656 could almost entirely recover the Aß1-42 (icv)-impaired cognitive function to the normal level and showed better behavioral performance than donepezil. The evaluation of the Aß1-42 total amount confirmed its anti-amyloidogenic profile. Moreover, 8012-9656 possessed blood-brain barrier (BBB) penetrating ability, a long T1/2, and low intrinsic clearance. Hence, the novel potential BChE inhibitor 8012-9656 can be considered as a promising lead compound for further investigation of anti-AD agents.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Benzimidazóis
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Butirilcolinesterase
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Inibidores da Colinesterase
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Fármacos Neuroprotetores
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Aminoquinolinas
Tipo de estudo:
Guideline
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2020
Tipo de documento:
Article