Studies on molecular properties prediction and histamine H3 receptor affinities of novel ligands with uracil-based motifs.
Studies on molecular properties prediction and histamine H3 receptor affinities of novel ligands with uracil-based motifs.
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DOI：
10.1016/j.ejmech.2014.09.011
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发表时间：
2014-10
影响因子：
6.7
通讯作者：
Luca Lipani;D. Odadzic;L. Weizel;J. Schwed;B. Sadek;H. Stark
中科院分区：
文献类型：
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作者：
Luca Lipani;D. Odadzic;L. Weizel;J. Schwed;B. Sadek;H. Stark
组胺H3受体（H3 R）在认知和记忆过程中起作用，并参与不同的神经系统疾病，包括阿尔茨海默病，精神分裂症和嗜睡症。因此，几种hH 3R拮抗剂/反向激动剂进入了主要集中发生疾病的广谱临床阶段。然而，许多其他有希望的候选物由于其药代动力学特征而失败，主要是因为其强亲脂性伴随低溶解度。对以前潜在的H3 R选择性拮抗剂/反向激动剂（例如pitolisant）的分析揭示了关于理化性质和药物相似性的有希望的结果。本文合成了一系列由哌啶-1-基或哌啶-1-基-丙氧基苯基偶联不同的尿嘧啶、胸腺嘧啶和5，6-二甲基尿嘧啶相关部分组成的新的hH 3R配体8 - 20，评价了它们在hH 3R上的结合特性以及不同的物理化学和药物样特性的估计。由于与嘧啶-2，4-（1H，3 H）-二酮上不同位置的偶联，hH 3Rs的亲和力和药物相似性参数得到了改善。例如，化合物9除了在hH 3R（pKi（hH 3R）= 8.14）处显示出高亲和力之外，还显示出分别为-4.36、3.47、0.34、4.63和1.54的clogS、clogP、LE、LipE和药物样评分值。此外，甲基取代的类似物17（pKi（hH 3R）= 8.15）显示LE、LipE和药物样评分值分别为-3.29，2.47，0.49，5.52和1.76。
The histamine H3receptor (H3R) plays a role in cognitive and memory processes and is involved in different neurological disorders, including Alzheimer's disease, schizophrenia, and narcolepsy. Therefore, several hH3R antagonists/inverse agonists entered clinical phases for a broad spectrum of mainly centrally occurring diseases. However, many other promising candidates failed due to their pharmacokinetic profile, mostly because of their strong lipophilicity accompanied with low solubility. Analysis of previous potential H3R selective antagonists/inverse agonists, e.g. pitolisant, revealed promising results concerning physicochemical properties and drug-likeness. Herein, a series of new hH3R ligands8–20consisting of piperidin-1-yl or piperidin-1-yl-propoxyphenyl coupled to different uracil, thymine, and 5,6-dimethyluracil related moieties, were synthesized, evaluated on their binding properties at the hH3R and the estimation of different physicochemical and drug-likeness properties. Due to the coupling to various positions at pyrimidine-2,4-(1H,3H)-dione, affinity at hH3Rs and drug-likeness parameters have been improved. For instance, compound9showed in addition to high affinity at the hH3R (pKi(hH3R) = 8.14) clogS, clogP, LE, LipE, and drug-likeness score values of −4.36, 3.47, 0.34, 4.63, and 1.54, respectively. Also, the methyl substituted analog17(pKi(hH3R) = 8.15) revealed LE, LipE and drug-likeness score values of −3.29, 2.47, 0.49, 5.52, and 1.76, respectively.