Design And Synthesis Of Compounds Acting On SEH Target

Soluble epoxide hydrolase（sEH）is widely distributed in organisms.It is involved in the metabolism of arachidonic acid and linoleic acid.sEH can be a target for the treatment of diseases such as inflammation,hypertension,stroke,diabetic retinopathy,etc.Therefore,inhibiting or degrading sEH may become a method for treating the above diseases.At present,representative inhibitors are t-AUCB,GSK2256294,GSK2982772.Particularly,t-AUCB has been widely used in pre-clinical research,GSK2256294 and GSK2982772have entered clinical research,but small molecule degraders for sEH have not been reported in the literature.In this paper,we have studied the action mode of t-AUCB on sEH and the structure-activity relationship of t-AUCB,found the urea structure fragment was an active essential group for binding to sEH.This paper took t-AUCB and GSK2256294 as lead compounds,adopted the principle of bioelectronic isosteric and combination to design three new sEH inhibitors（SM-X-1,SM-X-2,SM-X-3）.The study selected SM-X-2 as the representative compound,connected it with sEH in the computer-aided simulation software.The result showed the designed compounds could bind and play well with the enzyme.The study referred to the structural characteristics of other enzymes’small molecule degraders reported in literatures,linked the Pomalidomide（E₃Ligase Ligand）and t-AUCB（Recognize small molecules of sEH）with the structural fragment of 1-{4-[（methylamino）methyl]-1H-1,2,3-triazol-1-yl}propyl-2-one,designed sEH degradation agent SM-P-1.The study improved the synthetic route of the lead compound t-AUCB.Using trans-4-aminocyclohexanol and 4-fluorobenzonitrile as starting materials,through etherification reaction,hydrolysis reaction,condensation with adamantane isocyanate synthesized t-AUCB.Amantadine isocyanate was synthesized with amantadine hydrochloride and triphosgene.The reverse synthetic analysis method was used to determine the synthetic route of inhibitors and degradant.（1）Using ethyl trifluoroacetate as the starting material,through substitution,cyclization,acylation,chloroalkane substitution,deprotection,condensation synthesised sEH inhibitors.（2）Using L-glutamine as the starting material,through amino protection,cyclization,condensation,amino,acylation,azide,"click reaction"synthesized sEH degradation agent.Through the above route synthesized four target compounds:SM-X-1,SM-X-2,SM-X-3,SM-P-1.The structures were verified by¹H-NMR.The activity of the target compound is currently being tested.