Synthesis of Potent Non-imidazole Histamine H3-Receptor Antagonists

Abstract

Histamine has been converted into a non‐imidazole H3‐receptor histamine antagonist by addition of a 4‐phenylbutyl group at the Nα‐position followed by removal of the imidazole ring. The resulting compound, N‐ethyl‐N‐(4‐phenylbutyl)amine, remarkably has a Ki = 1.3 μM as an H3 antagonist. Using this as a lead compound, a novel series of homologous O and S isosteric tertiary amines was synthesised and structure‐activity studies furnished N‐(5‐phenoxypentyl)pyrrolidine (Ki = 0.18 ± 0.10 μM, for [3H]histamine release from rat cerebral cortex synaptosomes) which, more importantly, was active in vivo. Substitution of NO2 into the para position of the phenoxy group gave N‐(5‐p‐nitrophenoxypentyl)pyrrolidine, UCL 1972 (Ki = 39 ± 11 nM), ED50 = 1.1 ± 0.6 mg/kg per os in mice on brain tele‐methylhistamine levels.

The medicinal chemistry of novel H 3 antagonists

“…The 4-cyanophenyl group has appeared in other non-imidazole series [4,8], and also showed high potency in the benzofuran series, especially when appropriately incorporated into the 5-or 6-position of the benzofuran ring. The benzofurans had about equal or greater potency than the closest homologous acyclic biphenyl-nitrile propyloxyamine analogs in 5 of 8 cases.…”

“…These are now pharmacological standards [2], but are likely to be inappropriate for clinical use due to their inhibition of CYP 450 enzymes [3]. To address this liability, non-imidazole H 3 antagonists have recently been designed [4]. Many of these structures share a common pharmacophore of amine-alkylene-oxygen-aryl chain [5] ( Table 1).…”

Histamine H3 Receptor Antagonists Go to Clinics

“…A variety of secondary and generally tertiary amines, partly in form of aliphatic heterocycles, i.e. piperazino, pyrrolidino, 2-aminopyrrolidino, and morpholino elements, 112) was coupled instead of aromatic imidazole in order to find a suitable replacement structure. This resulted mostly in a piperidine moiety due to an increase in potency and decrease of pharmacokinetic interactions whereas larger substitutions or oxidation of this aliphatic heterocycle to some extent bears decline or loss in affinity.…”

Computational study of histamine H3-receptor antagonist with support vector machines and three dimension quantitative structure activity relationship methods

“…Yellow-coloured, blue-coloured and redcoloured regions near the heterocycle suggest that less bulk and suitable electronegative groups could be favourable to pK i activity. Ciproxifan class, UCL 1972 and FUB 649 with high in vitro and in vivo activity include these five-membered or six-membered heterocycle [34][35][36]. Yellow-coloured and bluecoloured regions covering phenyl show that bulk and positive charge groups are favourable to pK i activity.…”