Conversion of 4-cyanomethyl-pyrazole-3-carboxamides into CB1 antagonists with lowered propensity to pass the blood-brain-barrier
Conversion of 4-cyanomethyl-pyrazole-3-carboxamides into CB1 antagonists with lowered propensity to pass the blood-brain-barrier
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DOI：
10.1016/j.bmcl.2009.12.003
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发表时间：
2010-01-15
影响因子：
2.7
通讯作者：
Hogberg, Thomas
中科院分区：
文献类型：
--
作者：
Receveur, Jean-Marie;Murray, Anthony;Hogberg, Thomas
已经从相应的腈化合物制备了一系列酰胺、脒和酰亚胺，以提供与中枢作用的利莫那班相比具有显著更低的亲脂性、更高的极性表面积和改善的血浆/脑比的CB 1受体的有效拮抗剂和反向激动剂。对ADME和体内药理学性质的广泛研究导致选择酰胺系列，特别是4-（4-氟苯基）哌啶-4-醇衍生物D4。外围设备的明显改进。尽管不能排除中枢效应对肥胖小鼠体重显著减轻的某些作用，但观察到其作用小于利莫那班。(C)2009爱思唯尔有限公司保留所有权利。
A series of amides, amidines and amidoximes have been made from the corresponding nitrile compounds, to provide potent antagonists and inverse agonists for the CB1 receptor with considerably lower lipophiliciy, higher polar surface area and improved plasma/brain ratios compared to the centrally acting rimonabant. Extensive investigations of ADME and in vivo pharmacological properties led to selection of the amide series and specifically the 4-(4-fluorophenyl)piperidin-4-ol derivative D4. A clear improvement in the peripheral pro. le over rimonabant was seen, although some contribution of central effect on the pronounced weight reduction in obese mice cannot be ruled out. (C) 2009 Elsevier Ltd. All rights reserved.