Efficient Approaches to S-alkyl-N-alkylisothioureas and Application to Novel Histamine H3R Antagonists.
S-Alkyl-N-alkylisothiourea compounds, which contain various cyclic amines, were synthesized using 3-phenylpropionyl isothiocyanate (PPI) to discover novel non-imidazole histamine H3 receptor (H3R) antagonists. The synthetic route was improved remarkably by using 2-nitrophenylacetyl isothiocyanate (NPAI). Among the synthesized compounds, N-[4-(4-chlorophenyl)butyl]-S-[3-piperidin-1-yl)propyl]isothiourea (1k, OUP-186) exhibited potent and selective antagonism against human H3R but not human H4R, in vitro. Of particular interest, they did not show antagonism for the histamine release in rat brain microdialysis in vivo, suggesting species-selective differences in antagonist affinities. Furthermore, in silico docking studies of OUP-186 and its C2-homolog (OUP-181) in human/rat H3Rs suggested that the structural difference of antagonist-docking sites between human and rat H3Rs was attributable to the Ala122/Val122 mutation.
Laboratory of Pharmaceutical Organic Chemistry, Osaka University of Pharmaceutical Sciences.
Hiroki
H
Yoneyama
Daisuke
D
Yamamoto
Atsushi
A
Yamatodani
Shinya
S
Harusawa
D000818:Animals; D001921:Brain / Q000378:metabolism; D055808:Drug Discovery; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D009154:Mutation; D051381:Rats; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3 / Q000235:genetics; D000074040:Receptors, Histamine H4; D013045:Species Specificity; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C418607:HRH4 protein, human; D054828:Histamine H3 Antagonists; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4; D013890:Thiourea