Details

Autor(en) / Beteiligte

• Lipani, Luca
• Odadzic, Dalibor
• Weizel, Lilia
• Schwed, Johannes-Stephan
• Sadek, Bassem
• Stark, Holger

Titel

Studies on molecular properties prediction and histamine H3 receptor affinities of novel ligands with uracil-based motifs

Ist Teil von

• European journal of medicinal chemistry, 2014-10, Vol.86, p.578-588

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• 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. [Display omitted] •New histamine H3 receptor (H3R) ligands with uracil-based motifs were synthesized.•Their hH3R binding affinities were determined on membranes of HEK-293 cells.•Ligands 9 and 17 showed high affinity at the hH3R.•Ligands 9 and 17 revealed promising physicochemical and drug-likeness properties.