Identification of new functional inhibitors of acid sphingomyelinase using a structure-property-activity relation model
Identification of new functional inhibitors of acid sphingomyelinase using a structure-property-activity relation model
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DOI：
10.1021/jm070524a
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发表时间：
2008-01-24
影响因子：
7.3
通讯作者：
Gulbins, Erich
中科院分区：
文献类型：
--
作者：
Kornhuber, Johannes;Tripal, Philipp;Gulbins, Erich
一些有机弱碱可诱导酸性鞘磷脂酶（ASM）从溶酶体内膜脱离并随后失活，因此可作为功能性ASM抑制剂。本研究的目的是建立一个结构-性能-活性关系（SPAR）模型，以确定能够功能性抑制ASM的探针的结构和物理化学特征。高pK(a)和高对数P值是ASM功能抑制的必要条件，但不是充分条件。实验数据支持了一个额外的因子的要求，这是ASM功能抑制所必需的。该因子k与最基本氮原子的位阻有关，并可能调节质子化氮原子在溶酶体内表面的自由呈现。在研究过程中，我们鉴定了26种新的功能性ASM抑制剂，包括多赛平63、氟西汀104、马普替林109、去甲替林114、帕罗西汀118、舍曲林124、舒洛地尔125和特非那定127。
Some organic weak bases induce a detachment from inner lysosomal membranes and subsequent inactivation of acid sphingomyelinase (ASM) and thus work as functional ASM inhibitors. The aim of the present investigation was to develop a structure-property-activity relation (SPAR) model in order to specify the structural and physicochernical characteristics of probes capable of functionally inhibiting ASM. High pK(a) and high log P values are necessary but not sufficient preconditions for functional inhibition of ASM. The experimental data supported the requirement of an additional factor, which is necessary for functional inhibition of ASM. This factor k is related to the steric hindrance of the most basic nitrogen atom and presumably modulates the free presentation of a protonated nitrogen atom at the inner lysosomal surface. During the course of the study, we characterized 26 new functional ASM inhibitors, including doxepine 63, fluoxetine 104, maprotiline 109, nortriptyline 114, paroxetine 118, sertraline 124, suloctidil 125, and terfenadine 127.