D-Amino Acid Homopiperazine Amides: Discovery of A-320436, a Potent and Selective Non-Imidazole Histamine H3-Receptor Antagonist

Structure‐activity relationships of homopiperazine‐containing alkoxybiaryl nitriles employing various D‐amino acid moieties and their N‐furanoyl analogues were undertaken. This led to A‐320436, a potent and selective non‐imidazole H3‐receptor antagonist possessing balanced affinity for both rat and human H3‐receptors. This compound was shown to demonstrate in vitro and in vivo functional antagonism and is non‐neurotoxic at doses (i.p.) up to 163 mg/kg in a general observation test.