Diamine-based human histamine H3 receptor antagonists: (4-Aminobutyn-1-yl)benzylamines

A series of (4-aminobutyn-1-yl)benzylamines were prepared and the SAR around three key areas: (1) the amine attached to the butynyl linker (R3R4N–); (2) the benzylamine moiety (R1R2N–); and (3) the point of attachment of the benzylamine group (R1R2N– in the ortho, meta, or para positions) was examined. One compound, 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine (9s) was chosen for further profiling and found to be a selective histamine H3 antagonist with desirable drug-like properties. Ex vivo receptor occupancy studies established that 9s does occupy H3 binding sites in the brain of rats after oral administration. Subcutaneous doses of 9s (10 mg/kg) given during the natural sleep phase demonstrated robust wake-promoting effects.

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