4-Benzyl-1H-imidazoles with Oxazoline Termini as Histamine H₃ Receptor Agonists

Abstract

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.

Synthesis and NMR Analysis of 1,4‐Disubstituted 1,2,3‐Triazoles Tethered to Pyridine, Pyrimidine, and Pyrazine Rings

“…The pyrimidine nitrogen chemical shifts in the (4-pyrimidyl)methylenetriazole series 5 (δ = 291 ppm, Table 5, entries [30][31][32][33] are in agreement with literature data for 4-alkylpyrimidines (δ ≈ 291 ppm). [34,40] Unfortunately, the applied resolution of the 1 H-…”

“…A modified literature procedure, previously used for the reduction of the analogous benzyl alcohol derivatives, was applied. [30] The results are collected in Table 4. [a] Yield of isolated pure product.…”

Investigation of the Histamine H3 Receptor Binding Site. Design and Synthesis of Hybrid Agonists with a Lipophilic Side Chain

“…The combined organic layer was dried (Na 2 SO 4 ), evaporated, and purified with SiO 2 column chromatography (EtOAc/hexane = 2:3, then 1:1) to give 20 as a white solid (2.75 g, quant). 1 2-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-2-(1-trityl-1H-imidazol-4-yl)acetic Acid (21). A solution of 20 (2.75 g, 5.17 mmol) in 2-ethoxyethanol (5 mL) was added to the 40% KOH aqueous solution (20 mL), and the mixture was stirred at 100°C overnight.…”

“…15 Interestingly, H3 agonists of another type, possessing a less basic side chain or highly lipophilic moiety in place of the terminal basic nitrogen atom, have been discovered, as represented by immethridine 5, UCL 1470 8, and our compound 1. 10,13,[16][17][18][19][20][21] We have found that the introduction of an alkylated benzene ring to the terminal nitrogen atom of histamine, 4-(2-(N-(alkylphenyl)amino)ethyl)-1H-imidazole derivatives, partially maintained the agonistic activity of histamine. 10 Noticeably, para CF 3 and para t-Bu substituents on the benzene ring improved the H3 receptor affinity, and the alteration of its aminoethyl spacer part to the thioether of 1 increased the agonistic efficacy.…”

A simple method for iodination of heterocyclic compounds using HIO4/NaCl/silica gel/H2SO4 in water

“…Iodinated aromatic heterocycles are an important class of intermediates in organic synthesis which are extensively utilized in the medicinal chemistry and process development groups of pharmaceutical companies and in academic laboratories [1][2][3][4][5][6][7][8].…”