ganstigmine and Alzheimer-Disease

Ganstigmine (CHF-2819) is being developed by Chiesi as a potential treatment for neurodegenerative and cognitive disorders. The drug was in phase IIa studies in the US for senile dementia associated with Alzheimer's disease (AD) by mid-2000, and phase IIb trials in AD patients were scheduled for early 2001, with these ongoing in 2002.

Topics: Alkaloids; Alzheimer Disease; Animals; Carbamates; Clinical Trials as Topic; Drugs, Investigational; Humans; Technology, Pharmaceutical

Topics: Acetylcholine; Adult; Alkaloids; Alzheimer Disease; Animals; Carbamates; Cholinesterase Inhibitors; Clinical Trials, Phase II as Topic; Cognition Disorders; Dose-Response Relationship, Drug; Humans; Male; Rats

Ganstigmine is an orally active, geneserine derived, carbamate-based acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. The crystal structure of the ganstigmine conjugate with Torpedo californica acetylcholinesterase (TcAChE) has been determined at 2.40 A resolution, and a detailed structure-based analysis of the in vitro and ex vivo anti-AChE activity by ganstigmine and by new geneserine derivatives is presented. The carbamoyl moiety is covalently bound to the active-site serine, whereas the leaving group geneseroline is not retained in the catalytic pocket. The nitrogen atom of the carbamoyl moiety of ganstigmine is engaged in a key hydrogen-bonding interaction with the active site histidine (His440). This result offers an explanation for the inactivation of the catalytic triad and may account for the long duration of action of ganstigmine in vivo. The 3D structure also provides a structural framework for the design of compounds with improved binding affinity and pharmacological properties.

Topics: Acetylcholinesterase; Administration, Oral; Alkaloids; Alzheimer Disease; Animals; Binding Sites; Brain; Carbamates; Cholinesterase Inhibitors; Crystallization; Crystallography, X-Ray; Drug Evaluation, Preclinical; Enzyme Activation; Male; Mice; Models, Molecular; Molecular Conformation; Stereoisomerism; Structure-Activity Relationship; Torpedo

Ganstigmine, a new acetylcholinesterase inhibitor, was incubated with rat liver microsomes and the resulting metabolites were identified by high-performance liquid chromatographic/mass spectrometric (HPLC/MS) and HPLC/MS/MS analyses. The results showed the formation of eight main metabolites, among which geneseroline and molecules corresponding to mono-hydroxylated, demethylated and reduced ganstigmine. The metabolic profile drawn for humans, dog and monkey showed a pattern very similar to that of rat: only in the case of liver dog microsomes higher amounts of geneseroline and of a metabolite identified as demethylated and reduced drug were detected.

Topics: Alkaloids; Alzheimer Disease; Animals; Carbamates; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Dogs; Humans; Hydroxylation; Macaca fascicularis; Male; Mass Spectrometry; Methylation; Microsomes, Liver; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Species Specificity