Projects / Programmes
Butyrylcholinesterase inhibitors for alleviating symptoms of Alzheimer's disease
| Code |
Science |
Field |
Subfield |
| 1.09.00 |
Natural sciences and mathematics |
Pharmacy |
|
| Code |
Science |
Field |
| B740 |
Biomedical sciences |
Pharmacological sciences, pharmacognosy, pharmacy, toxicology |
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
Alzheimer's disease, butyrylcholinesterase, enzyme inhibitors, drug discovery and development, structure-based drug design, innovative approach
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
33908 |
PhD Urban Košak |
Pharmacy |
Head |
2018 - 2020 |
58 |
Organisations (1)
Abstract
Memory and cognitive deficits of patients with AD are the result of severely decreased brain levels of ACh. Currently approved ChEs inhibitors in AD therapy (donepezil, galantamine and rivastigmine) alleviate symptoms of the disease by increasing brain levels of ACh. They achieve this by preventing the breakdown of ACh through inhibition of the enzymes that hydrolyze it. These enzymes are called ChEs and two types are known: AChE and BChE. Donepezil, galantamine, rivastigmine and other AChE inhibitors however, have a major drawback. They inhibit AChE not only in the brain but also in the PNS and ANS. It is the inhibition of AChE in the PNS and ANS which is the cause of adverse cholinergic effects (nausea, diarrhea, vomiting, and tremors) of these drugs. This limits both their dosing and clinical efficacy in advanced stages of AD. The shortcoming of currently approved ChEs for alleviating symptoms of AD can be overcome using selective BChE inhibitors which raise brain levels of ACh and improve memory and cognitive performance of mice without any cholinergic adverse effects.
The goal of this Project is to develop selective reversible inhibitors of BChE with the potential to be developed into novel drugs for alleviating the symptoms of AD. Using structure-based drug design techniques, we will first design and then synthesize novel selective BChE inhibitors that will increase ACh levels in the brain and produce procognitive effects in vivo without producing adverse cholinergic effects. We expect to develop two advanced lead compounds with low-nanomolar to picomolar activities against huBChE and procognitive activity in vivo. Compounds developed in this project will provide a valuable contribution in pursuit of a clinical candidate; the latter will represent an important foundation for further development into active pharmaceutical substance.
We will publish the results of this Project in peer-reviewed journals in the fields of Medicinal Chemistry, Organic Chemistry and Neuroscience. We will also present the results of this project in form of oral and poster presentations at Slovene and international and scientific conferences. Promising inhibitors of BChE will also be the subject of patent applications.
Significance for science
The proposed research project is important because it strives to discover a new drug in a very important therapeutic area of neurodegenerative diseases. The research project will be a contribution in drug discovery of innovative drugs for alleviating the symptoms of AD. As populations age due to increasing life expectancy, the number of people with AD is expected to reach staggering numbers. AD is thus a very serious global challenge for drug discovery. Currently, AD cannot be prevented or cured. It is thus imperative that academic research groups focus their research toward preclinical development of drugs for alleviating symptoms of AD and develop lead compounds that can then be progressed further by and/or in collaboration with the pharmaceutical industry.
This research project will contribute immensely to the Slovenian pharmaceutical industry as the researchers, which will participate in the proposed research project, will gain the know-how for autonomous creative and innovative work in pharmaceutical industry. Despite the current generic nature of the Slovenian pharmaceutical industry, new lead compounds resulting from the proposed research project will be a good starting point for development of innovative drugs in cooperation of the Slovenian and international pharmaceutical industry. This is imperative due to ongoing globalization of Slovenian pharmaceutical industry (e.g. merger of Lek d.d. with Novartis). This research project will thus importantly contribute to the socio-economic aspect of science. Additionally, the results of the research project will be published in high-ranked international journals with SCI Impact Factor and international patent applications.
Significance for the country
The proposed research project is important because it strives to discover a new drug in a very important therapeutic area of neurodegenerative diseases. The research project will be a contribution in drug discovery of innovative drugs for alleviating the symptoms of AD. As populations age due to increasing life expectancy, the number of people with AD is expected to reach staggering numbers. AD is thus a very serious global challenge for drug discovery. Currently, AD cannot be prevented or cured. It is thus imperative that academic research groups focus their research toward preclinical development of drugs for alleviating symptoms of AD and develop lead compounds that can then be progressed further by and/or in collaboration with the pharmaceutical industry.
This research project will contribute immensely to the Slovenian pharmaceutical industry as the researchers, which will participate in the proposed research project, will gain the know-how for autonomous creative and innovative work in pharmaceutical industry. Despite the current generic nature of the Slovenian pharmaceutical industry, new lead compounds resulting from the proposed research project will be a good starting point for development of innovative drugs in cooperation of the Slovenian and international pharmaceutical industry. This is imperative due to ongoing globalization of Slovenian pharmaceutical industry (e.g. merger of Lek d.d. with Novartis). This research project will thus importantly contribute to the socio-economic aspect of science. Additionally, the results of the research project will be published in high-ranked international journals with SCI Impact Factor and international patent applications.
Most important scientific results
Final report
Most important socioeconomically and culturally relevant results
Final report
