Synthesis, pharmacology and molecular modeling of N-substituted 2-phenyl-indoles and benzimidazoles as potent GABAA agonists

被引:67
作者
Falco, Jose Luis [1 ]
Pique, Maria [1 ]
Gonzalez, Miguel [1 ]
Buira, Irma [1 ]
Mendez, Eva [1 ]
Terencio, Jose [1 ]
Perez, Cristina [1 ]
Princep, Marta [1 ]
Palomer, Albert [1 ]
Guglietta, Antonio [1 ]
机构
[1] Ferrer Int SA, Div Med Chem, E-08028 Barcelona, Spain
关键词
zolpidem; zaleplon; indiplon; non-benzodiazepinic; GABA-A receptor; indoles; benzimidazoles; ADME; volsurf; catalyst; combinatorial chemistry;
D O I
10.1016/j.ejmech.2006.03.031
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Among the known non-benzodiazepine hypnotic drugs, Zolpidem (1 a), Indiplon (2a) and Zaleplon (2b) have shown high affinity and selectivity for the a, subunit of the GABA-A receptor. Our group has performed pharmacophoric and ADMET-prediction studies to evaluate a virtual library of new molecules based on privileged structures. Among these, we have synthesized a library of N-substituted indoles and a library of N-substituted benzimidazoles. Afterwards, in vitro screening and in vivo spontaneous motor activity in mice has revealed molecules with good in vitro affinities for the a, receptor and potent in vivo induction of sedation. (c) 2006 Elsevier SAS. All rights reserved.
引用
收藏
页码:985 / 990
页数:6
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