ABSTRACT
A series of novel non-peptidic furin inhibitors containing amidinohydrazone moieties has been synthesized under interaction of dialdehydes, the derivatives of ethylene diethylvanillin ethers, with aminoguanidine bicarbonate. Two aryl cycles were bridged by 1,2-ethylene-, 1,4-buthylene- or 1,4-dimethylenebenzene-group. The compounds have been found to inhibit furin. The antifurin activity was shown to grow with the increase of the length and/or hydrophobicity of the bridge. The most potent compound, containing in the bridge the lypophylic benzene cycle was found to inhibit the activity of furin with Ki = 0.51 microM.
Subject(s)
Aldehydes/chemical synthesis , Furin/antagonists & inhibitors , Guanidines/chemical synthesis , Hydrazones/chemical synthesis , Serine Proteinase Inhibitors/chemical synthesis , Coumarins/chemistry , Furin/chemistry , Humans , Hydrophobic and Hydrophilic Interactions , Kinetics , Molecular Structure , Oligopeptides/chemistry , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Static Electricity , Structure-Activity RelationshipABSTRACT
A series of 5-amino-1H-pyrazoles was synthesized and studied as inhibitors of furin. The most potent compound, 5-amino-4-acetylamino-3-(4-methylphenylamino)1H-pyrazole, was found to retard the activity of furin by mixed-type inhibition with K = 288 microM. These findings permit to plan new ways for chemical modifications of the 5-amino-1H-pyrazole structure and design more potent furin inhibitors of non-peptide nature.
