Nıemann-pıck hastalığında kullanılan ilaçlara genel bakış, etki mekanizmaları ve yeni potansiyel ilaçların tasarlanması

Niemann Pick disease is one of the lysosomal storage disorders which negatively affect the metabolism and give rise to genetic mutations. There are four forms of this disease: Niemann-Pick Type A, B, C, and D. In contrast, the metabolic basis of Types C and D Niemann?Pick disease, genetically distinct from Niemann?Pick Type A and B. Lysosomal/late endosomal sequestration of endocytosed low density lipoprotein (LDL)-derived cholesterol is considered the hallmark phenotypic feature of the Niemann-Pick Type C lesion, together with a block or delay of LDL-induced cholesteryl ester formation in living cells. A decrease in cholesterol content within the LSOs can be possible by one or a combination of the following mechanisms: (1) increase in the cholesterol efflux from the LSOs; (2) decrease in the uptake of cholesterol; (3) decrease in the hydrolysis of cholesteryl esters by LAL. Considering on the second mechanism to execute might have reasonable two options: (1) decreasing absorbed cholesterol level by inhibition of NPC1L1; (2) down-regulating NPC1L1 gene expression. Previous studies have shown that down-regulation of NPC1L1 gene expression is possible activations of PPARs in vitro both in human and mouse models. In the present study, this second option is evaluated and studied on PPARs agonists for exploring a possible treatment NPC disease. To create a new scaffold Compound 1, 1a, 2, 2a, 3, 4, 5, 5a and 6 were synthesized by modification of AL26-18, lead compound, which had derived from clofibrate due to fibrates are one of the most known-studied group as PPAR agonists. On the lead compound especially has been focused on the aromatic portion and synthesis of isoster compounds that are Comp. 1a, 2a and 5a for modification. Biological activity results show that all compounds have good business competitiveness full or partial, respectively on PPAR? and PPAR?, compared to the AL26-18 (Comp. 1). In some cases, the activity on PPAR? proves to be even better compared to the compounds used as reference. According to these studies, some of these compounds could be effective for treating NPC disease. Key Words: Niemann?Pick type C1 (NPC1), PPARs, clofibrate