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A series of novel N-(4-pyridinyl)-1H-indol-1-amines and other heteroaryl analogs was synthesized and evaluated in tests to determine potential utility for the treatment of Alzheimer's disease. From these compounds, N-propyl-N-(4-pyridinyl)-1H-indol-1-amine (besipirdine, 4c) was selected for clinical development based on in-depth biological evaluation. In addition to cholinomimetic properties based initially on in vitro inhibition of [3H]quinuclidinyl benzilate binding, in vivo reversal of scopolamine-induced behavioral deficits, and subsequently on other results, 4c also displayed enhancement of adrenergic mechanisms as evidenced in vitro by inhibition of [3H] clonidine binding and synaptosomal biogenic amine uptake, and in vivo by reversal of tetrabenazine-induced ptosis. The synthesis, structure-activity relationships for this series, and the biological profile of 4c are reported.

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A novel series of substituted (pyrroloamino)pyridines was synthesized, and the compounds were evaluated for cholinomimetic-like properties in vitro (inhibition of [3H]quinuclidinyl benzilate binding) and in vivo (reversal of scopolamine-induced dementia) as potential agents for the treatment of Alzheimer's disease. Compounds displaying significant activity were more broadly evaluated, which revealed the presence of a desirable adrenergic component of activity. The synthesis and structure-activity relationships for this series is presented, along with the biological profiles of selected compounds.