Basic information

Investigator: RNDr. Tomáš Petrásek, Ph.D.
Main recipient: University Hospital Hradec Králové
Co-recipient: National Institute of Mental Health (NIMH), 
Research period: 01/01/2026 – 12/31/2029
Total budget: 15,183,000 CZK
NIMH budget: 7,439,000 CZK
Supported by: AZV (Czech Health Research Council)

Annotation

Alzheimer's disease (AD) remains the most pressing unmet medical need in neurology, with current treatments providing only limited symptomatic relief. Emerging evidence highlights the significant role of butyrylcholinesterase (BChE) in AD progression, especially as acetylcholinesterase (AChE) aktivity diminishes in later stages. BChE is increasingly recognized for its involvement not only in cholinergic dysfunction but also in broader pathophysiological processes including appetite regulation via the ghrelin pathway. This project seeks to develop novel, highly selective BChE inhibitors as promising preclinical drug candidates for AD treatment. By employing a multidisciplinary approach, we aim to profile these candidates comprehensively. Key objectives include the determination of BChE inhibition potency to draw detailed structure-activity relationship studies. In addition, cytotoxicity, cardiotoxicity, and genotoxicity assessments will be conducted to ensure compound safety. The project will also involve comprehensive in vivo evaluation to define toxicity, pharmacokinetic, and pharmacodynamic profiles of selected lead candidates. The clinical relevance of this research is highlighted by the urgent need for effective symptomatic treatments, particularly for patients in advanced AD stages where BChE inhibition shows therapeutic promise. By developing selective BChE inhibitors, this project aims to improve cognitive outcomes, enhance nutritional status through ghrelin regulation, and mitigate depression symptoms, ultimately reducing the symptomatic burden of AD. Furthermore, this project aligns with precision medicine principles, striving to tailor therapies to individual genetic profiles to enhance efficacy and minimize risks. Through its innovative approach, this research is poised to deliver meaningful insights iinto AD treatment and contribute to the development of novel therapeutics addressing this critical global healthcare challenge.

The primary objective of this project is to develop novel, highly selective butyrylcholinesterase (BChE) inhibitors as promising preclinical drug candidates for Alzheimer's disease (AD) treatment. The project employs a multidisciplinary approach integrating medicinal chemistry, in vitro characterization, and in vivo validation to comprehensively profile these candidates. Specifically, the project will involve detailed structure-activity relationship (SAR) studies to guide rational drug design. Furthermore, a detailed assessment of cytotoxicity, cardiotoxicity, and genotoxicity will ensure compound safety. To increase the likelihood of successful outcomes, the project will pursue parallel development of two distinct families of BChE inhibitors, mitigating the risk of failure if one branch faces challenges. In vivo evaluations will further assess toxicity, pharmacokinetics, and pharmacodynamics to identify optimal lead candidates with strong translational potential. The project’s clinical relevance is reinforced by the urgent need for effective symptomatic treatments, particularly in advanced AD stages where BChE inhibition may deliver therapeutic benefits. The proposed research further aligns with precision medicine principles, aiming to tailor therapeutic strategies to individual genetic profiles to improve efficacy and reduce adverse effects. By developing selective BChE inhibitors, this project aims to improve cognitive function, address malnutrition through ghrelin regulation, and alleviate depressive symptoms, collectively reducing the symptomatic burden of AD. Through this innovative and integrated approach, the project aspires to deliver novel therapeutics that respond to a critical global healthcare challenge, and bring valuable insights into AD treatment strategies.