Methods for glycosylation inhibition using amino-benzoic acids and derivatives
AssigneesThe Rockefeller University, Alteon Inc.
InventorsPeter C. Ulrich, Anthony Cerami, Dilip R. Wagle
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Abstract
The present invention relates to compounds, compositions and methods for inhibiting nonenzymatic cross-linking (protein aging). Accordingly, a composition is disclosed which comprises an agent capable of inhibiting the formation of advanced glycosylation endproducts of target proteins by reacting with a carbonyl moiety of the early glycosylation product of such target proteins formed by their initial glycosylation. The method comprises contacting the target protein with the composition. Both industrial and therapeutic applications for the invention are envisioned, as food spoilage and animal protein aging can be treated.
Claims33
A method for inhibiting the advanced glycosylation of a target protein comprising contacting the target protein with an effective amount of composition comprising a compound selected from the group consisting of compounds of the formula ##STR29## wherein R.sub.1 is a hydroxy, amino or hydrazino group, or a group of the formula
- --NR.sub.4 R.sub.5,
- wherein R.sub.4 is hydrogen or lower alkyl, and R.sub.5 is an alkyl group of 1-20 carbon atoms, a hydroxy lower alkyl group, a cycloloweralkyl group or a heterocyclic group containing 4-7 ring members and 1-3 heteroatoms, or R.sub.4 and R.sub.5 together with the nitrogen form a morpholino, piperidinyl, or piperazinyl group;
- R.sub.2 is 0-2 amino groups, or a hydrazino group, a hydrazinosulfonyl group, or an amidino group;
- R.sub.3 is hydrogen or a hydroxy group;
- with the proviso that when R.sub.1 is hydroxy, then R.sub.3 is a hydroxy group;
- with the further proviso that when R.sub.1 is hydrazino, then there must be at least two non-hydrogen substituents on the phenyl ring;
- and with the further proviso that when R.sub.3 is hydrogen, then R.sub.5 can also be an aminoimino, guanidyl, aminoguanidinyl or diaminoguanidyl group;
- their pharmaceutically acceptable acid addition salts;
- and mixtures thereof, and
- a carrier therefor.
A method for treating an animal to inhibit the formation of advanced glycosylation endproducts of a target protein within said animal, said method comprising administering to an animal in need of said treatment an effective amount of a pharmaceutical composition, said pharmaceutical composition comprising a compound selected from the group consisting of compounds of the formula ##STR30## wherein R.sub.1 is a hydroxy, amino or hydrazino group, or a group of the formula
- --NR.sub.4 R.sub.5,
- wherein R.sub.4 is hydrogen or lower alkyl, and R.sub.5 is an alkyl group of 1-20 carbon atoms, a hydroxy lower alkyl group, a cycloloweralkyl group or a heterocyclic group containing 4-7 ring members and 1-3 heteroatoms, or R.sub.4 and R.sub.5 together with the nitrogen form a morpholino, piperidinyl, or piperazinyl group;
- with the proviso that when R.sub.3 is hydrogen, then R.sub.5 can also be an aminoimino, guanidyl, aminoguanidinyl or diaminoguanidyl group;
- R.sub.2 is 0-2 amino groups, or a hydrazino group, a hydrazinosulfonyl group, or an amidino group;
- R.sub.3 is hydrogen or a hydroxy group;
- with the proviso that when R.sub.1 is hydroxy, then R.sub.2 is a single amino group and R.sub.3 is a hydroxy group;
- and further with the proviso that when R.sub.1 is hydrazino, then there must be at least two non-hydrogen substituents on the phenyl ring;
- their pharmaceutically acceptable acid addition salts;
- and mixtures thereof, and
- a carrier therefor.
A method of inhibiting the discoloration of teeth resulting from non-enzymatic browning in the oral cavity which comprises administration of an amount effective to inhibit the formation of advanced glycosylation endproducts of a composition comprising a compound selected from the group consisting of compounds of the formula ##STR31## wherein R.sub.1 is a hydroxy, amino or hydrazino group, or a group of the formula
- --NR.sub.4 R.sub.5,
- wherein R.sub.4 is hydrogen or lower alkyl, and R.sub.5 is an alkyl group of 1-20 carbon atoms, a hydroxy lower alkyl group, a cycloloweralkyl group or a heterocyclic group containing 4-7 ring members and 1-3 heteroatoms, or R.sub.4 and R.sub.5 together with the nitrogen form a morpholino, piperidinyl, or piperazinyl group;
- with the proviso that when R.sub.3 is hydrogen, then R.sub.5 can also be an aminoimino, guanidyl, aminoguanidinyl or diaminoguanidyl group;
- R.sub.2 is 0-2 amino groups, or a hydrazino group, a hydrazinosulfonyl group, or an amidino group;
- R.sub.3 is hydrogen or a hydroxy group;
- with the proviso that when R.sub.1 is hydroxy, then R.sub.2 is a single amino group and R.sub.3 is a hydroxy group;
- and further with the proviso that when R.sub.1 is hydrazino, then there must be at least two non-hydrogen substituents on the phenyl ring;
- their pharmaceutically acceptable acid addition salts;
- and mixtures thereof, and
- a carrier therefor.
Dependencies are inferred from the claim text.