Browsing by Subject "heteroaromaatti"

Prolyl oligopeptidase (POP) is a serine peptidase found at high concentrations in the brain, which cleaves short proline-containing peptides at the carboxyl side of proline. POP activity has been shown to differ between healthy people and ones suffering from certain neurodegenerative diseases. Amongst its other functions, it has been shown to accelerate α-synuclein aggregation. Inhibiting the enzyme prevents this acceleration. Many highly potent peptidic POP inhibitors, based on the enzyme’s natural substrates, have been synthesized. One of the problems with many of these peptide-like inhibitors is their inability to penetrate the blood-brain barrier efficiently. Recently, a new surprisingly potent non-peptidic inhibitor based on a novel heteroaromatic scaffold was discovered. There was a need to synthesize analogues of this inhibitor in order to gain a better understanding of the structure-activity relationship for compounds based on the new scaffold. Unfortunately, the heteroaromatic scaffold is relatively unstable without a stabilizing substituent. The aim of this research was synthesizing stable analogues, primarily by replacing the original heteroaromatic ring with other, more stable heteroaromatic rings. It was hypothesized that the activity of the original compound could be retained, as heteroaromatics can often act as bioisosteres of each other. Multiple close analogues containing the new heteroaromatic rings were successfully synthesized and tested. Although they were considerable more stable compared to the original compound, there was a significant decrease in potency. However, the new compounds were not completely inactive, and they provided useful information on the viability and importance of several different substituents. Furthermore, measuring the IC50 value is not enough to evaluate their overall effect on POP, since the inhibition of the proteolytic activity of POP does not seem to correlate with the inhibition of its other functions. Further investigation and development of the new compound series is needed.