Table 1.

Summary of ChEIs in preclinical and clinical development.

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.