Identification of 2-arylbenzimidazoles as potent human histamine H4 receptor ligands

2,4-Diaminopyrimidines as histamine H4 receptor ligands—Scaffold optimization and pharmacological characterization

“…On the one hand, H 4 R binding in the low nanomolar concentration range has been reported for these compounds but, on the other hand, they show high structural similarity to H 3 R antagonists. 27 The atypical neuroleptic clozapine has become a lead in H 4 R research (pK i = 6.8) 28 despite exhibiting high affinities to multiple biogenic amine receptors. 29 It is thought that it mainly mediates its antipsychotic effects via dopamine D 2 -like receptors as well as serotonin 5-HT 2 receptor subtypes though clozapine exhibits substantial affinity for other biogenic amine receptors such as histamine H 1 and adrenergic a 1 receptors.…”

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…This compound has low nanomolar affinity for the human H 4 receptor (Lane et al, 2012). Further benzimidazole-containing compounds were described in a series of patents from Johnson & Johnson (New Brunswick, NJ) Lee-Dutra et al, 2006;Edwards et al, 2007a,b). The benzimidazole scaffold in these compounds is typically linked to a substituted phenyl or heterocycle.…”

Histamine H4 Receptor: A Novel Therapeutic Target for Immune and Allergic Responses

“…Pfizer Inc. had successfully replaced the N-methylpiperazine moiety of 26 with an octahydropyrrolo [3,4-c]pyrrole developing the final compound (5-fluoro-4-methyl-1H-benzo[d]imidazol-2-yl)((3aR,6aS)-5-methylhexahydropyrrolo [3,4-c]pyrrol-2(1H)-yl) methanimine (27) [83]. Compound 6-chloro-2-(4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-1H-benzo[d] imidazole (28), a benzimidazole compound, was synthesized from HTS efforts from Johnson and Johnson [84,85]. A very extensive series of compounds, 28 and N-(4-(4-methyl-1,4-diazepan-1-yl)butyl)-4-(7-methyl-1H-benzo[d]imidazol-2-yl) pyridin-2-amine (29), were synthesized by alterations of the benzimidazole structures [86][87][88].…”