DEVELOPMENT OF A NEW PHYSICOCHEMICAL MODEL FOR BRAIN PENETRATION AND ITS APPLICATION TO THE DESIGN OF CENTRALLY ACTING H-2-RECEPTOR HISTAMINE-ANTAGONISTS
DEVELOPMENT OF A NEW PHYSICOCHEMICAL MODEL FOR BRAIN PENETRATION AND ITS APPLICATION TO THE DESIGN OF CENTRALLY ACTING H-2-RECEPTOR HISTAMINE-ANTAGONISTS
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DOI：
10.1021/jm00398a028
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发表时间：
1988-03-01
影响因子：
7.3
通讯作者：
WILKS, TJ
中科院分区：
文献类型：
--
作者：
YOUNG, RC;MITCHELL, RC;WILKS, TJ
本文提出了一种设计中枢作用药物的合理方法，其基础是比较三种典型的组胺H2受体拮抗剂与三种脑穿透药物可乐定（6）、美托咪明（7）和丙咪嗪（8）的理化性质。在大鼠的平衡脑/血液浓度比的均方根值和分配参数Δ之间发现了良好的相关性。log P，定义为log P（1-辛醇/水）-log P（环己烷/水），这表明脑渗透可能通过降低整体氢键能力而得到改善。该模型已被用作指导设计新的脑穿透H2拮抗剂的系统结构修饰的代表不同结构类型的H2拮抗剂。虽然在西咪替丁（1）、雷尼替丁（9）和噻替丁（10）的同类物中实现了脑渗透的显著增加，但没有发现具有可接受的H2拮抗剂活性组合的化合物（豚鼠心房中的-log KB> 7.0）。和脑渗透（稳态脑/血浓度比> 1.0）。相反，N-[[（哌啶基-甲基）苯氧基]丙基]乙酰胺（30）的结构修饰产生了几种有效的新型化合物，它们很容易穿过血脑屏障。其中之一，唑隆替丁（SK&F 95282，41），其-log KB为7.46，稳态脑/血比为1.4，已被鉴定用于研究脑中组胺能H2受体机制。Δ的比较log P值与20种结构不同的化合物的脑/血比率的对数的关系证实了高度显著的相关性，并支持该模型的一般有效性。
A rational approach to the design of centrally acting agents is presented, based intially upon a comparison of the physicochemical properties of three typical histmaine H2 receptor antagonists which do not readily cross the blood-brain barrier with those of the three brain-penetrating drugs clonidine (6), mepyramine (7), and imipramine (8). A good correlation was found between the logarithms of the equilibrium brain/blood concentration ratios in the rat and the partition parameter, .DELTA. log P, defined as log P (1-octanol/water)-log P (cyclohexane/water), which suggests that brain penetration might be improved by reducing overall hydrogen-bonding ability. This model has been employed as a guide in the design of novel brain-penetrating H2 antagonists by the systematic structural modification of representatives of different structural types of H2 antagonists. Although marked increases in brain penetration amongst congeners of cimetidine (1), ranitidine (9), and tiotidine (10) were achieved, no compound was found with an acceptable combination of H2 antagonist activity (-log KB in the guinea pig atrium > 7.0). and brain penetration (steady-state brain/blood concentration ratio > 1.0). Conversely, structural modification of N-[[(piperidinyl-methyl)phenoxy]propyl]acetamide (30) led to several potent, novel compounds which readily cross the blood-brain barrier. One of these, zolontidine (SK&F 95282, 41), whose -log KB is 7.46 and steady-state brain/blood ratio is 1.4, has been identified for use in studying histaminergic H2 receptor mechanisms in brain. Comparison of .DELTA. log P values with the logarithms of the brain/blood ratios for 20 structurally diverse compounds for which data became available confirms a highly significant correlation and supports the general validity of this model.