Discovery of substituted benzyl tetrazoles as histamine H3 receptor antagonists

A series of potent and subtype selective H3 receptor antagonists containing a novel tetrazole core and diamine motif is reported. A one-pot multi-component Ugi reaction was utilised to rapidly develop the structure–activity relationships (SAR) of these compounds. Optimisation for liver microsome stability (t1/2 >60 min), minimal CYP inhibition (IC50 >50 μM) and high cell permeability (Caco-2 Papp >20 × 10−6 cm/s) identified several compounds with drug-like properties.

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