Medicinal chemistry

 

Preparation and study of new promising imidazopyridine ligands

The serotonin 5-HT6 receptor (5-HT6R) belongs to the superfamily of G protein-coupled receptors (GPCRs). The 5-HT6R is exclusively localized in the central nervous system, predominantly in hippocampus, striatum, nucleus accumbens and prefrontal cortex. Its enrichment in those brain regions suggests an important role in memory and cognition processes. Pro-cognitive effects of two 5-HT6R antagonists, Idalopirdine (Lu-AE58054) and Intepirdine (SB-742457), were unequivocally demonstrated in Phase II clinical trials in patients with mild to moderate AD with treatment with the acetylcholine esterase inhibitor donepezil. Intepirdine and another 5-HT6R antagonist, Landipirdine, are currently under evaluation in Phase II trials in patients with dementia with Lewy bodies and Parkinson’s disease dementia.


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Structural requirements for designing potent and selective 5-HT6R ligands might be summarized into a positive ionizable nitrogen atom attached to a flat aromatic core ring system which is linked to a second distant aromatic ring mostly through a tetrahedral sulfonyl group. Only few efforts have been paid on replacing the sulfonyl group by its bioisosteric methylene group. Based on these findings, we applied a scaffold-hopping approach to design a novel N-benzyl 3H-imidazo[4,5-b] and 3H-imidazo[4,5-c]pyridine derivatives as potent and selective 5-HT6R neutral antagonists. We evaluated the in vitro affinity of synthesized compounds for 5-HT6Rs, functional profile and selectivity panel, followed by ADMET and pharmacokinetic properties for the most promising derivative. Finally, the pro-cognitive activity of selected compound has been evaluated in the novel object recognition (NOR) task in rats by measuring its ability to reverse drug-induced memory deficits.

Preparation of conjugates with purine CDK inhibitors

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Little or no specificity to cancer cells is one of the most serious problems of traditional chemotherapy of cancer as it leads to systemic toxicity. The systemic toxicity of conventional chemotherapy causes serious side effects and is also one of the limiting factors of treatment efficiency. The use of small molecule delivery systems is a promising approach which can decrease the systemic toxicity of cytotoxic drugs to rapidly dividing normal cells. Tumor targeting delivery systems have been intensively studied in the last three decades and represent one of the promising approaches for increasing of chemotherapy selectivity together with decreasing of systemic toxicity. Selective drug delivery is based on frequent overexpression of many receptors in tumor cells, which can serve as targets to deliver cytotoxic agent selectively into tumor. The relatively selective transport into tumor cells can be realized with the use of conjugates of cytotoxic agent and tumor recognition moiety.

Synthesis of fluorescently labeled compounds for chemical biology

TOC_uprava_2Visualization of small molecules in cells becomes an essential tool in drug discovery. The most commonly used method is fluorescent microscopy in which the studied molecule is equipped with a fluorescent label and the method allows for direct visualization of cellular uptake and distribution of the drug within the cell. A number of various conjugates of small molecules with fluorescent tags were reported to date with the application as probes, photosensitizers or luminescence switches and sensors. We are focusing on development of conjugates for visualization in cell, especially for promising biologically active compounds, such as triterpenes or 3-hydroxyquinolinones.

Synthesis of PROTAC conjugates

Obrázek1The PROTAC concept is based on the preparation of conjugates consisting of two main parts connected through a suitable linker, which is typically an ethylene-oxy-based aliphatic chain. One part of the conjugate interacts with the protein of interest, whereas the other binds to a component of E3 ubiquitin ligase. The phthalimide family is often employed as a part of PROTACs to hijack CRBN to target proteins. Pharmacological targeting of protein kinases has been validated as an effective therapeutic strategy, and over 37 kinase inhibitor drugs have received approval for clinical use in certain cancers. However, specific resistance often reduces the sensitivity of targeted kinases to drugs during therapy, and therefore novel molecules or approaches are intensively sought. Kinase degradation induced by PROTACs thus provides an interesting alternative not only for mechanistic studies or therapy but also for kinases with kinase-independent functions.