School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
Bioorg Med Chem. 2010 Feb;18(3):1045-53. doi: 10.1016/j.bmc.2009.12.052. Epub 2010 Jan 6.
Isosorbide-2-carbamate-5-esters are highly potent and selective butyrylcholinesterase inhibitors with potential utility in the treatment of Alzheimer's Disease (AD). They are stable in human plasma but in mouse plasma they undergo hydrolysis at the 5-ester group potentially attenuating in vivo potency. In this paper we explore the role of the 5-position in modulating potency. The focus of the study was to increase metabolic stability while preserving potency and selectivity. Dicarbamates and 5-keto derivatives were markedly less potent than the ester class. The 2-benzylcarbamate-5-benzyl ether was found to be potent (IC(50) 52 nM) and stable in the presence of mouse plasma and liver homogenate. The compound produces sustained moderate inhibition of mouse butyrylcholinesterase at 1mg/kg, IP.
5-氨基甲酰基-2-异氰酸根合-1,3-二氧戊环酯类化合物是高效且具有选择性的丁酰胆碱酯酶抑制剂，在治疗阿尔茨海默病（AD）方面有潜在的应用价值。它们在人血浆中稳定，但在鼠血浆中，它们会在 5-酯基处发生水解，从而潜在地降低体内活性。在本文中，我们探讨了 5 位在调节活性方面的作用。研究的重点是在保持活性和选择性的同时提高代谢稳定性。双氨基甲酸酯类和 5-酮衍生物的活性明显低于酯类化合物。发现 2-苄基氨基甲酰基-5-苄基醚具有较强的活性（IC50 为 52 nM），并且在鼠血浆和肝匀浆中稳定。该化合物以 1mg/kg，IP 的剂量给药时，可使鼠丁酰胆碱酯酶持续中度抑制。
