SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF N-PROPYL-N(4-PYRIDINYL)-1H-INDOL-1-AMINE (BESIPIRDINE) AND RELATED ANALOGS AS POTENTIAL THERAPEUTIC AGENTS FOR ALZHEIMERS-DISEASE

A series of novel N-(4-pyridinyl)-1H-indol-1-amines and other heteroar yl analogs was synthesized and evaluated in tests to determine potenti al utility for the treatment of Alzheimer's disease. From these compou nds, N-propyl-N-(4-pyridinyl)-1H-indol-1-amine (besipirdine, 4c) was s elected for clinical development based on in-depth biological evaluati on. In addition to cholinomimetic properties based initially on in vit ro inhibition of [H-3]quinuclidinyl benzilate binding, in. vivo revers al of scopolamine-induced behavioral deficits, and subsequently on oth er results, 4c also displayed enhancement of adrenergic mechanisms as evidenced in vitro by inhibition of [H-3]clonidine binding and synapto somal biogenic amine uptake, and in vivo by reversal of tetrabenazine- induced ptosis. The synthesis, structure-activity relationships for th is series, and the biological profile of 4c are reported.