title: Studies on molecular properties prediction and histamine H3 receptor affinities of novel ligands with uracil-based motifs.
abstract: 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.
authors.affiliation: 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.
authors.forename: Luca
authors.initials: L
authors.lastname: Lipani
authors.affiliation: 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.
authors.forename: Dalibor
authors.initials: D
authors.lastname: Odadzic
authors.affiliation: Biocenter, Institute of Pharmaceutical Chemistry, Johann-Wolfgang Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
authors.forename: Lilia
authors.initials: L
authors.lastname: Weizel
authors.affiliation: Biocenter, Institute of Pharmaceutical Chemistry, Johann-Wolfgang Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Universitaetsstr. 1, 40225 Duesseldorf, Germany.
authors.forename: Johannes-Stephan
authors.initials: JS
authors.lastname: Schwed
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, P.O. Box 17666, United Arab Emirates. Electronic address: bassem.sadek@uaeu.ac.ae.
authors.forename: Bassem
authors.initials: B
authors.lastname: Sadek
authors.affiliation: Biocenter, Institute of Pharmaceutical Chemistry, Johann-Wolfgang Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany; Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Universitaetsstr. 1, 40225 Duesseldorf, Germany. Electronic address: stark@hhu.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
mesh_terms: D004305:Dose-Response Relationship, Drug; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D054828:Histamine H3 Antagonists; D008024:Ligands; D018100:Receptors, Histamine H3; D014498:Uracil
keywords: Antagonists; Drug-likeness; GPCR; Histamine H(3) receptor; Pyrimidine-2,4-(1H,3H)-dione