Gelatinase inhibitors and prodrugs
AssigneeUniversity of Notre Dame du Lac
InventorsMayland Chang, Shahriar Mobashery, Mijoon Lee
Life of this patent
Estimating the term…
Abstract
The invention provides compounds, compositions, and methods for the treatment of diseases, disorders, or conditions that are modulated by matrix metalloproteinases (MMPs). The disease, disorder, or condition can include, for example, stroke, neurological disorders, or ophthalmological disorders. The treatment can include administering a compound or composition described herein, thereby providing a prodrug compound that metabolizes to an active MMP inhibitor in vivo. The MMP inhibition can be selective inhibition, for example, selective inhibition of MMP-2, MMP-9, and/or MMP-14. Thus, the invention provides non-mutagenic prodrug compounds of the formulas described herein that result in the inhibition of MMPs upon in vivo administration.
Claims17
A method of treating a chronic wound comprising administering to a patient in need of such treatment an effective amount of a compound of Formula A:
- wherein X is O, NH or —S—NH—, and R1 is:
- wherein
- L is O, NH, —OCH2O—, or —C(═O)O—CH2O—;
- each Y is independently —NH2, —CO2H, —P(═O)(OH)2, —OP(═O)(OH)2, Het, or a guanidine moiety;
- Het is a 5 or 6 membered heterocyclic ring comprising 1, 2, or 3 heteroatoms selected from O, N, S, or P, wherein the ring optionally includes one or two sites of unsaturation and the ring is optionally substituted with 1, 2, or 3 oxo, halo, nitro, or methyl groups;
- and
- R3 is an amino acid or a linear or branched chain of two to five amino acids, linked to X or the carbonyl of R1 by a nitrogen or sulfur atom;
- or a salt thereof;
- wherein the compound has an aqueous solubility of at least 5 mg/mL;
- thereby treating the chronic wound.
A method of treating a chronic wound comprising administering to a patient in need of such treatment an effective amount of a compound of Formula I:
- wherein
- X is O, NRa, or —S—NH—;
- Ra is H or (C1-C4)alkyl;
- R1 is —(C═O)-L-(CH2)(m-1)—CH3, —(C═O)—(CH2)m—Y;
- —(C═O)-L-(CH2)m—Y;
- —(C═O)—(CHRx)—NHRy;
- —P(═O)(OH)2;
- an amino acid;
- or a linear or branched chain of two to five amino acids;
- L is O, NH, —OCH2O—, or —C(═O)O—CH2O—;
- Rx is H or —(CH2)mY;
- Ry is H or —(C═O)—CH(NH2)—(CH2)mY;
- m is 1-6;
- each Y is independently —NH2, —CO2H, —P(═O)(OH)2, —OP(═O)(OH)2, Het, or a guanidine moiety;
- Het is a 5 or 6 membered heterocyclic ring comprising 1, 2, or 3 heteroatoms selected from O, N, S, or P, wherein the ring optionally includes one or two sites of unsaturation and the ring is optionally substituted with 1, 2, or 3 oxo, halo, nitro, or methyl groups;
- each R2 is independently hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, aryl, heteroaryl, carboxy, cyano, nitro, halo, trifluoromethyl, trifluoromethoxy, SRz, SO2N(Rz)2, NRzRz, or COORz;
- wherein each Rz is independently H, (C1-C6)alkyl, (C1-C6)alkanoyl, (C6-C10)aroyl, aryl, aryl(C1-C6)alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, or optionally a nitrogen protecting group when covalently bonded to a nitrogen atom;
- and
- each n is independently 0, 1, 2, 3, or 4;
- or a salt thereof;
- and
- wherein the compound has an aqueous solubility of at least 5 mM;
- thereby treating the chronic wound.
A method of treating a chronic wound comprising administering to a patient in need of such treatment an effective amount of compound 6 or 11d:
- or a salt thereof;
- thereby treating the chronic wound.
Dependencies are inferred from the claim text.