Lipani Luca, Odadzic Dalibor, Weizel Lilia, Schwed Johannes-Stephan, Sadek Bassem, Stark Holger
Department of Drug Sciences, University of Catania, Viale A. Doria, 6, I-95125 Catania, Italy; Biocenter, Institute of Pharmaceutical Chemistry, Johann-Wolfgang Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
Biocenter, Institute of Pharmaceutical Chemistry, Johann-Wolfgang Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Eur J Med Chem. 2014 Oct 30;86:578-88. doi: 10.1016/j.ejmech.2014.09.011. Epub 2014 Sep 6.
The histamine H3 receptor (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 ligands 8-20 consisting 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, compound 9 showed in addition to high affinity at the hH3R (pKi (hH3R) = 8.14) clog S, clog P, LE, LipE, and drug-likeness score values of -4.36, 3.47, 0.34, 4.63, and 1.54, respectively. Also, the methyl substituted analog 17 (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.
组胺H3受体（H3R）在认知和记忆过程中发挥作用，并涉及多种神经系统疾病，包括阿尔茨海默病、精神分裂症和发作性睡病。因此，几种人源H3R拮抗剂/反向激动剂进入了针对多种主要发生在中枢的疾病的临床阶段。然而，许多其他有前景的候选药物因其药代动力学特征而失败，主要是因为它们具有很强的亲脂性且溶解度低。对先前潜在的H3R选择性拮抗剂/反向激动剂（如匹莫林）的分析揭示了有关物理化学性质和药物相似性的有前景的结果。在此，合成了一系列由哌啶-1-基或哌啶-1-基-丙氧基苯基与不同的尿嘧啶、胸腺嘧啶和5,6-二甲基尿嘧啶相关部分偶联而成的新人源H3R配体8-20，并对它们与人源H3R的结合特性以及不同物理化学和药物相似性性质进行了评估。由于与嘧啶-2,4-(1H,3H)-二酮的不同位置偶联，人源H3R的亲和力和药物相似性参数得到了改善。例如，化合物9除了与人源H3R具有高亲和力（pKi（人源H3R）= 8.14）外，clog S、clog P、LE、LipE和药物相似性评分值分别为-4.36、3.47、0.34、4.63和1.54。此外，甲基取代类似物17（pKi（人源H3R）= 8.15）的LE、LipE和药物相似性评分值分别为-3.29、2.47、0.49、5.52和1.76。
