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

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 (pK_i (hH₃R) Combining double low line 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 (pK_i (hH₃R) Combining double low line 8.15) revealed LE, LipE and drug-likeness score values of -'3.29, 2.47, 0.49, 5.52, and 1.76, respectively.