Design,Synthesis And Sar Study Of Novel Non-purine Xanthine Oxidase Inhibitors

Xanthine oxidase is an important enzyme during the uric acid generation process,which catalyzes xanthine and hypoxanthine to uric acid and xanthine respectively.So far,only Allopurine and Febuxostat were approved by the FDA as a Gout treatments.Allopurine was launched by Glaxo Smithkine in 1963,and Febuxostat was launched by the Teijin Company in 2009.Febuxostat is excellent in treatment of gout,while its side effects can not be ignored.Therefor,it is of significance to develop new,low toxic and efficient non-purine xanthine oxidase inhibitors(XOI).Our group employed the Pharmacophore Model-based drug discovery strategy and found compound LXM-7 bearing 1H-imidazole-4-carboxylic acid-5-amides core was a novel class of XOI.Based on the core structure of LXM-7,three approaches were taken for in the pharmacophore exploration and structure optimization studies,including the phenylamide at C-4 position with optimal structure investigation,the carboxylic group at C-5 position with bioisostere replacement,as well as druggability and novelty optimization of the imidazole ring.The first modification kept 4-carboxylic acid fixed,and investigated the electric effect of meta or para substituted aniline to the bioactivity,we introduced cyclopropylamine to inspect the alicyclic amine to the bioactivity.And then we incorporated cinnamon amine to investigate the distance between the amides and phenyl to the activity.The second modification also kept imidazole acid,and investigated the electric effect and lipophicity of 3,4-bis substituted aniline to the bioactivity;we transfered aniline to indoleamine and investigate the aromatic to the bioactive-ty.Since the carboxy is difficult to penetrate the cell membrane,the third modification was carboxyl group bioisostereo replacement at C-4 position of the imidazole ring,with formamide,hydrazide,N-cyclopropyl carboxamide,N-methylcarboxamide,N-hydroxyformamide to derivative,we investigated the balance of activity and physicochemical properties.The fourth modification was the structure derivative of the imidazole ring,we introduced N-methyl to the imidazole ring,and investigated the interactions between NH and amino acid residues.We synthesized 34 compounds and tested the xanthine oxidase inhibitory activity,it showed that,when a strong electron withdrawing group(-CN,-NO2)at C-3 position of the aniline combined the lipophilic fragment(alkoxy,halogen,aliphaticamine)at C-4 position of the aniline,it was very beneficial for the activity;The most active compounds was 2-19,it's IC50 can up to 5.5 nM.we replaced aniline with cyclopropylamine,and it was completely inactive;we used cinnamylamine and 5-amino indole to replace aniline,the activity improve 10 to 100 times by contrast with LXM-7.Introduced carboxyl isostere,it's solubility increased,while the activity reduced.Nitrogen methylation of the imidazole ring,the compound was completely inactive.