Synthesis And Bioactivity Of Fluoroolefin Amine As SSAO/VAP-1 Inhibitors

SSAO/VAP-1 is a copper amine oxidase containing divalent copper,which is widely found in the endothelial cells of various organs and tissues in the human body.It is not only involved in the metabolism of biogenic and heterogenic primary amines,but also plays a role in adhesion molecules,leukocyte transport,regulation of glucose uptake and the balance of the environment in fat cells.SSAO activity is altered in a variety of human diseases,including diabetes,congestive heart failure,cirrhosis,alzheimer's disease,and certain inflammatory diseases,with most of its activity increased.Therefore,the development of SSAO/VAP-1inhibitors has become the focus of future research.Based on PXS-4728A of boehringer ingelheim company as lead compounds,this thesis explores the structure innovation by active group docking methods.We designed A,B segments to reconstruct them docking for alternative compounds.Active evaluation,its mechanism of action has also explored.Specific research contents and results are as follows:?1?N-tert-butyl-4-hydroxy-benzoyl amide was used as solid segment B,and the structure of segment A?fluoroacrylamide?was modified.The readily available amino acid fragments were used as raw materials for synthesis.A total of 15 compounds were obtained.?2?Fluoroallamine was used as fixed segment B,segment A?aryl substrate segment?was structured.The aryl rings of azacyclic ring,benzodiazacyclic ring and azacyclic azacyclic fragment were used as intermediates to synthesize 22 compounds,and their structures were determined by nuclear magnetism and mass spectrometry.?3?The activity of the compounds was evaluated by inhibition activity of SSAO/VAP-1in recombinat and Sprague Dawley rats,and of recombinat MAO-A and MAO-B,and pharmacokinetic assay.The results showed that fragment A was the active group,and its modification could easily lead to great reduction in the bioactivity or even inactivation.In the process of preserving fragment A and modifying fragment B,it was found that all the compounds with azacyclic ring,benzodiazepine and azacyclic fragment had good inhibition effects of SSAO/VAP-1 in vivo and in vitro,among which the 13k was similar to the lead compound in IC₅₀ value,and the pharmacokinetic data was superior to that of the lead compound.?4?The potential mechanism of action between ligand molecules and receptor proteins was elucidated by means of computer-aided drug design.This study showed that the active modification of PXS-4728a as the lead compound can be used as a potential method to synthesize SSAO/VAP-1 inhibitors,which provides a new approach for the design and development of efficient and low-toxicity SSAO/VAP-1 inhibitor.