1-Benzylbenzimidazoles: The discovery of a novel series of bradykinin B1 receptor antagonists

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Abstract

The design, synthesis, and structure–activity studies of a novel series of BK B1 receptor antagonists based on a 1-benzylbenzimidazole chemotype are described. A number of compounds, for example, 38g, with excellent affinity for the cynomolgus macaque and rat bradykinin B1 receptor were discovered.

Graphical abstract

The design, synthesis, and structure–activity studies of a novel series of BK B1 receptor antagonists based on a 1-benzylbenzimidazole chemotype are described. A number of compounds, for example, 38g, with excellent affinity for the cynomolgus macaque and rat BK B1 receptor were discovered.

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    But because of high molecular weight and poor oral bioavailability in rodents the phenethylbenzodiazepine moiety of 15 (Scheme 4) was replaced by benzimidazole core a low molecular weight surrogate, led to potent compound at both human and rat bradykinin B1 receptors with improved oral bioavailability. The 2-carboxamide group was important for the activity and a number of different linkers and amine groups like pyridine and piperidine moieties were studied but the combination of β-alanine linker and 2-imidazoline-5-aminopyridine group, however, led to the identification of compound 16 (Scheme 4) showing excellent potency with IC50 = 2 nM [43]. Similarly, Zischinsky et al. reported benzimidazole derivatives as small molecule bradykinin B1 receptor antagonist 17 (Scheme 4) with IC50 value 3500 nM.

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