64310-53-8Relevant academic research and scientific papers
Discovery of adamantyl ethanone derivatives as potent 11β- hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors
Su, Xiangdong,Pradaux-Caggiano, Fabienne,Thomas, Mark P.,Szeto, Michelle W. Y.,Halem, Heather A.,Culler, Michael D.,Vicker, Nigel,Potter, Barry V. L.
experimental part, p. 1026 - 1044 (2011/02/21)
11β-Hydroxysteroid dehydrogenases (11β-HSDs) are key enzymes regulating the pre-receptor metabolism of glucocorticoid hormones. The modulation of 11β-HSD type 1 activity with selective inhibitors has beneficial effects on various conditions including insulin resistance, dyslipidemia and obesity. Inhibition of tissue-specific glucocorticoid action by regulating 11β-HSD1 constitutes a promising treatment for metabolic and cardiovascular diseases. A series of novel adamantyl ethanone compounds was identified as potent inhibitors of human 11β-HSD1. The most active compounds identified (52, 62, 72, 92, 103 and 104) display potent inhibition of 11β-HSD1 with IC50 values in the 50-70 nm range. Compound 72 also proved to be metabolically stable when incubated with human liver microsomes. Furthermore, compound 72 showed very weak inhibitory activity for human cytochrome P450 enzymes and is therefore a candidate for in vivo studies. Comparison of the publicly available X-ray crystal structures of human 11β-HSD1 led to docking studies of the potent compounds, revealing how these molecules may interact with the enzyme and cofactor.
11-BETA-HYDROXYSTEROID DEHYDROGENASE INHIBITORS
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Page/Page column 79, (2008/06/13)
There is provided a compound having Formula (I ) R1-Z-R2 wherein R1 is a group selected from optionally substituted fused polycyclic groups, substituted alkyl groups, branched alkyl groups, and optionally substituted cycioalkyl groups Z is a linker which is or comprises a carbonyl group or a isostere of a carbonyl group R2 is selected from optionally substituted aromatic rings and optionally substituted heterocyclic rings wherein (a) R2 is a 2-substituted thiophene group, and/or (b) Z is a group of the formula -C(=O)-CR3R4-X-(CR5R6)n-, wherein X is selected from NR7, S, O, S=O, and S(=O)2, wherein n is 0 or 1 and/or (c) R1 is an adamantyl group and Z is or comprises an amide group, and/or (d) R1 is an adamantyl group and Z is or comprises a group of the formula -(CR8R9)p- NR10-S(=O)2-(CR11R12)q-, wherein p is 0 or 1 and q is 0 or 1 and/or (e) R1 is an adamantyl group and Z is or comprises a group of the formula -(CR13R14)V-Y- (CR15R16)W- where Y is a heteroaryl group in which a bond in the heteroaryl ring is a isostere of a carbonyl group, wherein v is o or 1 and w is 0 or 1 ; wherein each of R3, R4, R5, R6, R8, R9, R11, R12, R13, R14, R15 and R16, are independently selected from H, hydrocarbyl and halogen, wherein each of R7 and R10 are independently selected from H and hydrocarbyl.
