Ad Candidate Treatments For Drug Xq528 Derivatization And Conformational Restriction Analogues Design, Synthesis And Activity Research

Most of the drugs approved by FDA against Alzheimer's disease (AD) are based on "the cholinergic hypothesis", including AChE selective inhibitors and BChE selective inhibitors.(-)-Meptazinol phenylcarbamate(XQ528) developed by our team is an AChE selective inhibitor of phenylcarbamate kind, which has a novel mother nucleus. It has been recommended to be a promising drug in the National Drug Innovative Program, because of its multiple inhibiting effects on AChE and APP translation, as well as its anti-inflammatory abilities.We aim to study the effect of benzene ring's electrical property and steric hindrance of the leading compound, XQ528, on its activities and selectivities toward inhibiting AChE/BChE and APP translation.11 compounds were designed and synthesized. These compounds contain electron donor, electron-withdrawing and steric-hindrance substituents in some position of the phenyl group of the phenyl carbamoyl moieties. The derivatives were synthesized by esterification with (-)-meptazinol and substituted phenyl isocyanate which were gained from the reaction of substituted aniline, as starting materials, with triphosgene.The experimental result of ChE inhibitory activities shows that electron donating is beneficial to the inhibitory effect, while electron withdrawing is unfavorable to the activities. Among the target compounds, the AChE inhibitory activity of 9 is potent (IC50=0.026nM), better than XQ528, thus making it worthy of advanced research as a potent highly selective AChE inhibitor. Hydrophilic group, and steric-hindrance substituents(isopropyl group in especial) in para position of phenyl ring, were found to increase the selectivity toward BChE. The BChE selectivities and activities of 5 and 7 are better than the well-selling drug Rivastimine, with 833 and 1000 times more potency in inhibiting BChE, and 6 and 35 times more selectivity towards BChE. Further study on these compounds are also recommended.By analyzing the structures of current carbamate AChE inhibitors, we found that the distances between phenolic oxygen atom and the protonizable nitrogen atom are within a certain range. In order to discuss the relationship between the distance and the compound's AChE inhibitory activitiy, the pharmacophore's conformation was limited. The phenyl carbamate derivatives were designed from 1,2,3,4,5,6-hexahydro-azepino[4,3-b]indole and 1,2,3,4,5,6-hexahydroazepino[3,2-b]indole as mother nucleus. In the process of synthesis, R group of target compounds were changed from methyl to benzyl. Then, their synthesis simplicity and drug-likeness would be improved, as the molecule planarity was broken and the solubility was increased. In addition, the synthesis of intermediate 40 was improved. Fischer indole synthesis and oximation were combined into one step. Its yield rose from 48% to 62%. Finally, 6-benzyl-2-methyl-1,2,3,4,5,5a,6,10b-octahydroazepino[4,3-b]indol-9-yl phenylcarbamate(47) was synthesized. The primary experimental result of ChE inhibitory activities shows it is a moderate BChE selective inhibitor.We have synthesized 33 compounds totally, including 13 target compounds, all of which are novel ones.