Alzheimer's disease (AD) has been recognized as one of the most disabling conditions affecting the aged and is the major cause of dementia among elderly people. While numerous theories exist regarding the etiology of AD, the hypothesis that a defect in the cholinergic system is involved has received the most attention in terms of a therapeutic strategy. In support of this hypothesis, muscarinic agonists, cholinergic releasing agents, and cholinesterase inhibitors have shown activity in AD patients in experimental situations. Furthermore, a recent clinical report on the efficacy of the cholinesterase inhibitor 1,2,3,4-tetrahydro-9 acridinamine (THA, tacrine) created hope that at least a "first generation" of agents for the treatment of AD was at hand. The even more recent temporary suspension of THA from clinical trials in AD because of liver toxicity prompts us to report on a new compound, (f)-g-amino-1,2,3,4-tetrahydroacridin-1-01 maleate (1, HP-029), which is currently in phase I1 clinical trials for AD. We became interested in tacrine-like compounds quite some time ago as part of our program in AD. This interest was prompted by the unique mechanism by which THA has been shown to inhibit cholinesterase; it was, however, tempered by the known liver toxicity of THA. We suspected that the lipophilic nature of THA would cause it to accumulate in tissues (including the liver), leading to its observed toxicity. Accordingly, compound 1 was designed with chemical functionality that should limit its toxicity. It was predicted that the 1-hydroxyl group of 1, by providing a ready "handle" for glucuronide conjugation, might facilitate elimination and lessen toxicity without sacrificing the all-important abilities of the molecule to inhibit cholinesterase and cross the blood-brain barrier. Compound 1 exhibits a biochemical and pharmacological profile similar to THA and yet, in acute and subchronic toxicology studies, it is far less toxic than THA and is, until now, without measurable liver toxicity in humans. In view of these and other results, clinical trials were initiated with 1. In light of the recently reported results with THA, we feel it timely to report that upon completion of phase I with 1, an acceptable dose range for outpatient evaluation has been defined. Neither laboratory nor clinical evidence of drug-induced hepatotoxicity has been reported in 1396 subject days of exposure (normal young and elderly volunteers as well as in AD patients). Further studies to establish the safety and efficacy of 1 in AD are under way.