Studies on the development of 5-lipoxygenase activating protein (FLAP)inhibitors

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Thesis Type: Postgraduate

Institution Of The Thesis: Gazi Üniversitesi, Sağlık Bilimleri Enstitüsü, Turkey

Approval Date: 2014

Student: SERKAN LEVENT

Supervisor: ERDEN BANOĞLU

Open Archive Collection: AVESIS Open Access Collection

Abstract:

Leukotrienes (LT) are lipid mediators having significant roles on various diseases. FLAP has a crucial role on the biosynthesis of these mediators by acting as a bridge protein for efficient transfer of the substrat arachidonic acid (AA) to 5- lipoxygenase (5-LO). Therefore, inhibition of FLAP has become a substantial target for treatment of LT-based disorders. Based on the benzimidazole derivative lead structure (BRP-7) previously discovered by our research group, twenty-two final compounds having different substituents at C(5) position of the benzimidazole ring were designed and synthesized. Moreover, rasemic lead compound BRP-7 was separated into its enantiomers with a minimum 95% enantiomeric excess by using polimer-based chiral stationary phase (CSP) on HPLC. Structures of all compounds were elucidated by spectral techniques and elemental analysis, and their inhibitory effects on LT biosynthesis in human polimorfo nuclear leucocyte (PMNL) cells were investigated. Among them, 2-(((1-(2-chlorobenzyl)-2-(1-(4- isobutylphenyl)ethyl)-1H-benzimidazol-5-yl)oxy)methyl) benzonitrile (6f) is found to be the most active derivative with the IC50 value of 0,12 μM. Additionally, compounds 6j, 6p, 6u, 6v and 6y demonstrated higher activity on inhibition of LT biosynthesis than the lead compound BRP-7 (IC50 values of 0,12-0,23 μM). Meanwhile, the effects of individual enantiomers of the lead compound on LT biosynthesis were also investigated. IC50 values for (R)- and (S)-enantiomers were found to be 0,18 μM and 0,26 μM, respectively, while the IC50 value for racemate was 0,31 μM. In conclusion, we did not observe any drastic difference between 2- trifluoromethyl and 2-chloride substituted benzyl groups on N(1) position of the benzimidazole ring in terms of the biological activity. However, the presence of relatively small groups with possible hydrogen bonding and polar interactions at C(5) of the benzimidazole ring has contributed significantly to the observed biological activity.