基于次膦酸的NAALADase抑制剂的设计与药理活性

Design and pharmacological activity of phosphinic acid based NAALADase inhibitors.

作者信息

Jackson P F, Tays K L, Maclin K M, Ko Y S, Li W, Vitharana D, Tsukamoto T, Stoermer D, Lu X C, Wozniak K, Slusher B S

机构信息

Guilford Pharmaceuticals Inc., 6611 Tributary Street, Baltimore, Maryland 21224, USA.

出版信息

J Med Chem. 2001 Nov 22;44(24):4170-5. doi: 10.1021/jm0001774.

DOI:10.1021/jm0001774

PMID:11708918

Abstract

A novel series of phosphinic acid based inhibitors of the neuropeptidase NAALADase are described in this work. This series of compounds is the most potent series of inhibitors of the enzyme described to date. In addition, we have shown that these compounds are protective in animal models of neurodegeneration. Compound 34 significantly prevented neurodegeneration in a middle cerebral artery occlusion model of cerebral ischemia. In addition, in the chronic constrictive model of neuropathic pain, compound 34 significantly attenuated the hypersensitivity observed with saline-treated animals. These data suggest that NAALADase inhibition may provide a new approach for the treatment of both neurodegenerative disorders and peripheral neuropathies.

摘要

本研究描述了一系列新型的基于次膦酸的神经肽酶NAALADase抑制剂。该系列化合物是迄今为止所描述的该酶最有效的抑制剂系列。此外，我们已经表明这些化合物在神经退行性疾病的动物模型中具有保护作用。化合物34在大脑中动脉闭塞性脑缺血模型中显著预防了神经退行性变。此外，在神经性疼痛的慢性压迫模型中，化合物34显著减轻了盐水处理动物所观察到的超敏反应。这些数据表明，抑制NAALADase可能为治疗神经退行性疾病和周围神经病变提供一种新方法。