4-benzyl-1H-imidazoles with oxazoline termini as histamine H3 receptor agonists.
Research on the therapeutic applications of the histamine H3 receptor (H3R) has traditionally focused on antagonists/inverse agonists. In contrast, H3R agonists have received less attention despite their potential use in several disease areas. The lower availability of H3R agonists not only hampers their full therapeutic exploration, it also prevents an unequivocal understanding of the structural requirements for H3R activation. In the light of these important issues, we present our findings on 4-benzyl-1H-imidazole-based H3R agonists. Starting from two high throughput screen hits (10 and 11), the benzyl side chain was altered with lipophilic groups using combinatorial and classical chemical approaches (compounds 12-31). Alkyne- or oxazolino-substituents gave excellent affinities and agonist activities up to the single digit nM range. Our findings further substantiate the growing notion that basic ligand sidechains are not necessary for H 3R activation and reveal the oxazolino group as a hitherto unexplored functional group in H3R research.
Wijtmans
Maikel
M
Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Exact Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
Celanire
Sylvain
S
Snip
Erwin
E
Gillard
Michel R
MR
Gelens
Edith
E
Collart
Philippe P
PP
Venhuis
Bastiaan J
BJ
Christophe
Bernard
B
Hulscher
Saskia
S
van der Goot
Henk
H
Lebon
Florence
F
Timmerman
Henk
H
Bakker
Remko A
RA
Lallemand
Bénédicte I L F
BI
Leurs
Rob
R
Talaga
Patrice E
PE
de Esch
Iwan J P
IJ
D000818:Animals; D016466:CHO Cells; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D003412:Cricetulus; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D006168:Guinea Pigs; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007422:Intestines / Q000187:drug effects / Q000502:physiology; D008958:Models, Molecular; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011869:Radioligand Assay; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013329:Structure-Activity Relationship
D017442:Histamine Agonists; D007093:Imidazoles; D010080:Oxazoles; D018100:Receptors, Histamine H3; D003577:Cytochrome P-450 Enzyme System