INSULIN DERIVATIVES FOR DIABETES TREATMENT

摘要

Compounds, compositions, and methods for “smart” delivery of a therapeutic, prophylactic or diagnostic agent, such as glucose-mediated delivery of insulin through glucose-sensing insulin derivatives, are provided. The insulin derivatives bind serum albumin or agglomerate in vivo. The insulin derivatives effectively dissociate to release insulin in a hyperglycemic condition, where the complexation of glucose to a glucose-sensing element alters properties of the insulin derivative leading to the dissociation. The compounds, compositions, and methods provide a delivery strategy for both self-regulated and long-term diabetes management.

主权项

1. An insulin conjugate having the formula:
X1-X2 wherein X1 is insulin, an insulin analog, glucagon, GLP-1, or a GLP-1 agonist,
X2 is:(i) —CO—(CH2)—NH—CO—CR1R2,
wherein j is an integer from 3-25R1 is —NH—R12 or —NH—CO—CH2—CH2—CNR12—R32, where R32 is glucamine, gluconic acid, glucosamine, fructosamine, galactosamine, mannosamine, or other hexosamines,R12 is selected from the group consisting of hydrogen, —SO2alkyl, —SO2cycloalkyl, —SO2heterocycloalkyl, —SO2aryl, —SO2heteroaryl, —COalkyl, —COcycloalkyl, —COheterocycloalkyl, —COaryl, —COheteroaryl, —CONHalkyl, —CONHcycloalkyl, —CONHheterocycloalkyl, —CONHaryl, —CONHheteroaryl,wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are substituted or unsubstituted,
R2 is —(CH2)n—NH—CO—Rii or —(CH2)n—NH—SO2R11,n is an integer from 3-25, andR11 is a phenylboronic acid group;(ii) an oligomer comprising a plurality of monomers, wherein the monomers comprise a side chain, wherein the side chain comprises one or more phenylboronic acid groups, hydrophobic residues, hydrophilic neutral residues, hydrophilic charged residues, diol residues, fluorescent residues, and combinations thereof, wherein at least one of the side chains comprises a phenylboronic acid group;(iii) —CO—R6—R7,
wherein R6 is a linker or is not present,wherein R7 is a diol-containing group complexed to a hydrophobic phenylboronic acid (PBA) group, wherein the diol-containing group comprises one or more diols, wherein the hydrophobic PBA group comprises one or more PBA groups covalently linked to a hydrophobic group, wherein at least on diol and one hydrophobic PBA group form a boronic ester; or(iv) —CO—R8, wherein R8 is:
(a) -alkylene-R9 or -alkenyl-R9, wherein R9 is a phenylboronic acid group, wherein the alkylene or alkenyl group can be substituted or unsubstituted, wherein the number of carbons in the alkylene or alkenyl group is from 3 to 25,(b) —R13, wherein R13 is a bile acid, wherein one or more hydroxyls on the bile acid are derivatized with a phenylboronic acid group, or(c) —(CH2)r—NH—CO—CHR14—NH—CO—(CH2)8, wherein r is an integer from 3-25, wherein s is an integer from 3-25, wherein R14 is an amine-containing group comprising a phenylboronic acid group.