title: Benzylpiperidine variations on histamine H3 receptor ligands for improved drug-likeness.
abstract: Several hH3R antagonists/inverse agonists entered clinical phases for a broad spectrum of mainly centrally occurring diseases. Nevertheless, many promising candidates failed due to their pharmacokinetic profile, mostly because of their strong lipophilicity and their dibasic character. Analysis of previously, as potential PET ligands synthesized compounds (ST-889, ST-928) revealed promising results concerning physicochemical properties and drug-likeness. Herein, the synthesis, the evaluation of the binding properties at the hH3R and the estimation of different physicochemical and drug-likeness properties of further novel benzylpiperidine variations on H3R antagonists is described. Due to the introduction of various small hydrophilic moieties in the structure, drug-likeness parameters have been improved. For instance, compound 12 (ST-1032) showed in addition to high affinity at the H3R (pKi (hH3R)=9.3) clogS, clogP, LE, LipE, and LELP values of -2.48, 2.18, 0.44, 7.14, and 4.95, respectively. Also, the keto derivative 5 (ST-1703, pKi (hH3R)=8.6) revealed LipE and LELP values of 5.25 and 6.84, respectively.
authors.affiliation: Johann Wolfgang Goethe University, Institute of Pharmaceutical Chemistry, Biozentrum, Max-von-Laue-Str. 9, 60438 Frankfurt/Main, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wingen
authors.affiliation: Heinrich Heine University Duesseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, 40225 Duesseldorf, Germany.
authors.forename: J Stephan
authors.initials: JS
authors.lastname: Schwed
authors.affiliation: Johann Wolfgang Goethe University, Institute of Pharmaceutical Chemistry, Biozentrum, Max-von-Laue-Str. 9, 60438 Frankfurt/Main, Germany.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Isensee
authors.affiliation: Johann Wolfgang Goethe University, Institute of Pharmaceutical Chemistry, Biozentrum, Max-von-Laue-Str. 9, 60438 Frankfurt/Main, Germany.
authors.forename: Lilia
authors.initials: L
authors.lastname: Weizel
authors.affiliation: Heinrich Heine University Duesseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, 40225 Duesseldorf, Germany.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Zivković
authors.forename: Dalibor
authors.initials: D
authors.lastname: Odadzic
authors.affiliation: Johann Wolfgang Goethe University, Institute of Pharmaceutical Chemistry, Biozentrum, Max-von-Laue-Str. 9, 60438 Frankfurt/Main, Germany.
authors.forename: Dalibor
authors.initials: D
authors.lastname: Odazic
authors.affiliation: Heinrich Heine University Duesseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, 40225 Duesseldorf, Germany. Electronic address: stark@hhu.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
mesh_terms: D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D018100:Receptors, Histamine H3 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D006633:Histamine Antagonists; D008024:Ligands; D010880:Piperidines; D018100:Receptors, Histamine H3; C071293:1-benzylpiperidine
keywords: Antagonists; Drug-likeness; GPCR; Histamine H(3) receptor; Lipophilicity