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| Drug | Disposition |
|
| Physostigmine | First drug investigated; however, it is no longer used due to side effects, short half-life, and better treatment options. |
| Donepezil | Highly selective AChEI. Approved for mild, moderate, and severe AD. |
| Rivastigmine | Has dual bChEI and AChEI properties. Approved for mild-to-moderate AD. Patch formulation has reduced cholinergic-related side effects. |
| Galantamine | A lower potency AChEI with allosteric nicotinic receptor modulation properties. |
| Metrifonate | A highly selective AChEI that demonstrated a robust and significant clinical effect, but was abandoned after Phase III RCTs because of risk of neuromuscular dysfunction. |
| Phenserine | A derivative of physostigmine with a dual mechanism of action including anti-Aβ properties as well as AChEI. Despite a good safety profile, it did not achieve significant efficacy during Phase II trials. |
| Tolserine | A physostigmine derivative, has shown promise in the preclinical stages. |
| Esolerine | Another physostigmine derivative, is also a strong AChEI and favors AChE over BuChE greatly. It has not entered clinical trials. |
| NS2330 (tesofensine) | Robust preclinical efficacy and safety data. Early Phase II studies showed a positive signal on cognition. Follow-up RCTs for AD were discontinued in 2008 because of lack of clinical efficacy signal. It is currently being investigated as a treatment for obesity treatment. |
| Huperzine A | HupA is natural herb that is marketed as a supplement in the US. It acts as a ChEI. It is drug of choice for AD in China. Phase II trials in the US showed a modest but clinical significant effect on cognition in AD. |
| Huperzine B | HupB is less potent and selective than HupA, but it has a higher therapeutic index. |
| Nelumbo nucifera | The stamens of Nelumbo nucifera has demonstrated an improvement in memory in rats and favors AChE over BuChE. |
| Himatanthus lancifolius | A shrub with multiple medicinal purposes. The uliene in Himatanthus lancifolius is what is likely responsible for the significant AChE inhibitory effects. |
| Galangin | Galangin is a flavonoid that demonstrated significant inhibition of AChE. It has not been tested in human trials. |
| Donepezil hybrids | (1) Of the series of hybrids derived from Donepezil and AP2238, compounds 15, 21, and 22 demonstrated the most potential. Human studies have not been undertaken yet. |
| (2) The entire series of donepezil-tacrine hybrids showed more significant benefits than either parent drug alone. Human studies are planned. |
| Tacrine hybrids | (1) The beta-carboline derivatives (2A, 2B, 2C) and tacrine/ferulic acid hybrids (1A, 1B) were shown to have no efficacy in vivo, and 1B actually worsened the impairment in an scopolamine-induced in vivo model. Clinical development has not been pursued further. |
| (2) The tacrine-8-hdroxyquinoline hybrids showed potential in vitro, but the effects have yet to be shown in vivo. |
| Synthetic analogues | (1) The majority of the phenyl-5,6-dimethoxy-1-oxo-2,3-dihydro-1H-2-indenylmethanone analogues demonstrated significant AChEI in in vitro and in vivo models. |
| (2) N-alkyl-7-methoxytacrine hydrochlorides are also an area of interest as compounds 5–7 have more efficacy than THA and 7-MEOTA. |
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