TY - JOUR
T1 - Studies on molecular properties prediction and histamine H3 receptor affinities of novel ligands with uracil-based motifs
AU - Lipani, Luca
AU - Odadzic, Dalibor
AU - Weizel, Lilia
AU - Schwed, Johannes Stephan
AU - Sadek, Bassem
AU - Stark, Holger
N1 - Funding Information:
Supported by UAEU Program for Advanced Research (UPAR) 2013 Grant (# 31M126 ), UAE University . We greatly thank Prof. J.-C. Schwartz (Bioprojet, Saint-Grégoire, France) for providing HEK-293 cells stably expressing the recombinant human histamine H 3 receptor. Support for this work has been kindly given to HS by the EU COST Actions BM0806, BM1007, CM1103, and CM1207, DFG INST 208/664-1 FUGG as well as the Hesse LOEWE Schwerpunkte Fh-TMP, OSF and NEFF, the Else KrönerStiftung, TRIP, the Deutsches Konsortium für Translationale Krebsforschung (DKTK), and Deutsches Krebsforschungszentrum (DKFZ), Heidelberg.
Publisher Copyright:
© 2014 Elsevier Masson SAS.
PY - 2014/10/30
Y1 - 2014/10/30
N2 - 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) 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 (pKi (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.
AB - 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) 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 (pKi (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.
KW - Antagonists
KW - Drug-likeness
KW - GPCR
KW - Histamine H3 receptor
KW - Pyrimidine-24-(1H 3H)-dione
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U2 - 10.1016/j.ejmech.2014.09.011
DO - 10.1016/j.ejmech.2014.09.011
M3 - Article
C2 - 25218907
AN - SCOPUS:84907855670
SN - 0223-5234
VL - 86
SP - 578
EP - 588
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -