From pyrroles to 1-oxo-2,3,4,9-tetrahydro-1H-β-carbolines:: A new class of orally bioavailable mGluR1 antagonists
From pyrroles to 1-oxo-2,3,4,9-tetrahydro-1H-β-carbolines:: A new class of orally bioavailable mGluR1 antagonists
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DOI：
10.1016/j.bmcl.2007.01.055
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发表时间：
2007-04-15
影响因子：
2.7
通讯作者：
Vitulli, Giovanni
中科院分区：
文献类型：
--
作者：
Di Fabio, Romano;Micheli, Fabrizio;Vitulli, Giovanni
利用已知的吡咯衍生物的SAR，一类新的mGluR 1拮抗剂的设计取代吡咯核心与吲哚支架和随后的C-2位成三环β-咔啉模板环化。适当的探索的位置C-6与H-键受体基团的组合与庞大的/亲脂性部分耦合导致发现了一系列新的mGluR 1拮抗剂。这些化合物在急性和慢性疼痛的动物模型中，口服给药后表现出非竞争性行为、优异的药代动力学性质和良好的体内活性。(c)2007爱思唯尔有限公司保留所有权利。
Exploiting the SAR of the known pyrrole derivatives, a new class of mGluR1 antagonists was designed by replacement of the pyrrole core with an indole scaffold and consequent cyclization of the C-2 position into a tricyclic beta-carboline template. The appropriate exploration of the position C-6 with a combination of H-bond acceptor groups coupled with bulky/lipophilic moieties led to the discovery of a new series of mGluR1 antagonists. These compounds exhibited a non-competitive behavior, excellent pharmacokinetic properties, and good in vivo activity in animal models of acute and chronic pain, after oral administration. (c) 2007 Elsevier Ltd. All rights reserved.