Lisa Araki

Synthesis of imifuramine and its stereoisomers exhibiting histamine H3-agonistic activity

Abstract The four possible stereoisomers of a novel imidazole C-nucleoside derivative were synthesized by the efficient use of a PhSe group. Among them, (+)-4(5)-[(2R,5R)-5-(aminomethyl)tetrahydrofuran-2-yl]imidazole (imifuramine) was indicated as a novel type of histamine H 3 -agonist by a brain microdialysis method.

Synthesis and evaluation of N-alkyl-S-[3-(piperidin-1-yl)propyl]isothioureas: High affinity and human/rat species-selective histamine H3 receptor antagonists

S-Alkyl-N-alkylisothiourea compounds containing various cyclic amines were synthesized in the search for novel nonimidazole histamine H3 receptor (H3R) antagonists. Among them, four N-alkyl S-[3-(piperidin-1-yl)propyl]isothioureas 18, 19, 22, and 23 were found to exhibit potent and selective H3R antagonistic activities against in vitro human H3R, but were inactive against in vitro human H4R. Furthermore, three alkyl homologs 18-20 showed inactivity for histamine release in in vivo rat brain microdialysis, suggesting differences in antagonist affinities between species. In addition, in silico docking studies of N-[4-(4-chlorophenyl)butyl]-S-[3-piperidin-1-yl)propyl]isothiourea 19 and a shorter homolog 17 with human/rat H3Rs revealed that structural differences between the antagonist-docking cavities of rat and human H3Rs were likely caused by the Ala122/Val122 mutation.

Efficient approaches to S-alkyl-N-alkylisothioureas: syntheses of histamine H3 antagonist clobenpropit and its analogues.

S-Alkyl-N-alkylisothioureas were efficiently synthesized via synthetic approach (A) using 3-phenylpropionyl isothiocyanate (PPI). The utility of the approach was proved by the syntheses of clobenpropit, a potent histamine H(3) antagonist, and its analogues. Alternatively, clobenpropit could be prepared via intramolecular amide cleavage (B) with use of 2-nitrophenylacetyl isothiocyanate (NPAI).

Synthesis of two estradiol-imidazole C-ribonucleoside hybrid compounds exhibiting inhibitory effects against type 1 17β-hydroxysteroid dehydrogenase

Novel estradiol-imidazole C-nucleoside hybrid compounds 4a and 4b, which have C4-linked C o - and C 2 -imidazole ribonucleosides as adenosine mimics and amide bond linkers, were designed and synthesized based on EM-1745, an inhibitor of type 1 17β-hydroxysteroid dehydrogenase (17β-HSD1). Compounds 4a and 4b were also tested as enzyme inhibitors.

Synthesis of cis- or trans-2,4-Disubstituted Tetrahydrofurans Bearing Amino and Imidazole Groups by Efficient Use of the Modified or Standard Mitsunobu Cyclization: Synthetic Studies toward Novel Histamine H3-Ligands

R,4S) or (2S,4S)-4-Aminotetrahydrofuran-2-yl)imidazole ((-)-1a or (-)-1b) and its enantiomers ((+)-2a and (+)-2b) were synthesized by efficient use of the modified or standard Mitsunobu cyclization.