MODULATORS OF INSULIN RECEPTOR ACTIVITY

摘要

Methods to identify compounds which have at least one characteristic selected from the group consisting of a composition that (a) modulates the kinase activity of insulin receptor; and/or (b) potentiates the insulin activation of insulin receptor; and/or (c) potentiates the stimulation by insulin of cellular glucose uptake; and/or (d) stimulates the uptake of glucose in cells displaying the insulin receptor; and/or (e) lowers blood glucose in diabetic subjects; and/or (f) stimulates IRS-1 phosphorylation; and/or (g) stimulates PI3 kinase activity; and/or (h) stimulates GLUT-4 translocation; are described. Successful substances having such characteristics alter the conformation of the two-lobed cytoplasmic kinase domain or preferentially bind sites which have been identified as modulator binding sites in the insulin receptor beta chain. Also, modulation of the activity of the insulin receptor, enhancement of glucose uptake by cells, and other effects significant in the control and management of diabetes are accomplished using compounds of formula (1), wherein each Ar is independently an aromatic moiety; each A is independently a proton-accepting substituent; each R is independently a noninterfering substituent; m is 0, 1 or 2; n is 1-6; and each linker is independently -CH2-, -N=N-, -CH=CH-, -NHCO-, or -NHCONH- or an isostere thereof, wherein when n is 1, at least one Ar must comprise at least 2 fused aromatic rings. Compounds in the genus of formula (1) can also be used for structure activity studies to identify features responsible for the relevant activities.