INTRODUCTION: Gln-1062 (Memogain) is a pharmacologically inactive prodrug of galantamine. Owing to its lipophilic nature, it preferentially enters the brain, where it is cleaved into active galantamine. Gln-1062 is expected to have fewer peripheral side effects than other cholinesterase inhibitors, with improved effectiveness. METHODS: This was a double-blind, comparator and placebo-controlled, sequential cohort, single ascending dose study in 58 healthy subjects with Gln-1062 in doses of 5.5, 11, 22, 33, and 44 mg, compared with oral galantamine 16 mg and donepezil 10 mg. Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed. RESULTS: Gln-1062 doses up to 33 mg were well tolerated and induced a dose-dependent increase in the plasma concentrations of Gln-1062 and galantamine. Gln-1062 had a dose-dependent positive effect on verbal memory and attention, mainly in the first hours after drug administration. DISCUSSION: Gln-1062 was better tolerated than galantamine in doses with the same molarity and led to improved effects in cognitive tests. This is most likely caused by the more favorable distribution ratio between peripheral and central cholinesterase inhibition. These results give reason for further exploration of this compound.
Title: Nasal Application of the Galantamine Pro-drug Memogain Slows Down Plaque Deposition and Ameliorates Behavior in 5X Familial Alzheimer's Disease Mice Bhattacharya S, Maelicke A, Montag D Ref: J Alzheimers Dis, 46:123, 2015 : PubMed
The plant alkaloid galantamine is an established symptomatic drug treatment for Alzheimer's disease (AD), providing cognitive and global relief in human patients. However, as an acetylcholinesterase inhibitor, gastrointestinal side effects limit the dosage and duration of treatment. Memogain (Gln-1062), a pro-drug, liberates galantamine on cleavage by a carboxyesterase in the brain. The possibility to deliver Memogain intranasally may further circumvent side effects, allowing higher dosing compared to galantamine. In this study, the 5X Familial Alzheimer's Disease (5XFAD) mouse model was used to investigate the effect of chronic Memogain treatment on behavior and amyloid-beta (Abeta) plaque deposition in the brain. Chronic intranasal dosage of 6 mg/kg body weight twice daily was tolerated well, whereas the double dose caused body weight loss in males and was less effective in some behavioral tests. 8 weeks of chronic treatment resulted in improved performance in behavioral tests, such as open field and light-dark avoidance, and in fear conditioning already at mildly affected stages at the age of 18 weeks compared to untreated controls. Furthermore, after treatment a significantly lower plaque density in the brain, i.e., in the entorhinal cortex (reduction 20% females, 40% males) and the hippocampus (19% females, 31% males) at the age of 18 weeks was observed. These results show that nasal application of Memogain effectively delivers the drug to the brain with the potential to retard plaque deposition and improve behavioral symptoms in AD similar to the approved galantamine.
Memogain (Gln-1062) is an inactive pro-drug of galantamine, the latter being a plant alkaloid approved for the treatment of mild to moderate Alzheimer's disease. Memogain has more than 15-fold higher bioavailability in the brain than the same doses of galantamine. In the brain, Memogain is enzymatically cleaved to galantamine, thereby regaining its pharmacological activity as a cholinergic enhancer. In animal models of drug-induced amnesia, Memogain produced several fold larger cognitive improvement than the same doses of galantamine, without exhibiting any significant levels of gastrointestinal side effects that are typical for the unmodified drug and other inhibitors of cholinesterases, such as donepezil and rivastigmin. In the ferret, dramatically reduced emetic and behavioral responses were observed when Memogain was administered instead of galantamine. Based on these and other preclinical data, Memogain may represent an advantageous drug treatment for Alzheimer's disease, combining much lesser gastrointestinal side effects and considerably higher potency in enhancing cognition, as compared to presently available drugs.
