Method of regulating glucose metabolism, and reagents related thereto
AssigneesTrustees of Tufts College, 1149336 Ontario Inc., New England Medical Center Hospitals, Inc.
InventorsWilliam W. Bachovchin, Andrew G. Plaut, Daniel Drucker
Life of this patent
Estimating the term…
Abstract
The present invention provides methods and compositions for modification and regulation of glucose and lipid metabolism, generally to reduce insulin resistance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, hyperlipoprotein-emia (such as chylomicrons, VLDL and LDL), and to regulate body fat and more generally lipid stores, and, more generally, for the improvement of metabolism disorders, especially those associated with diabetes, obesity and/or atherosclerosis.
Claims88
A method for modifying glucose metabolism of an animal, comprising conjointly administering to the animal an inhibitor of dipeptidylpeptidase IV or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify the glucose metabolism of an animal but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonists, prolactin inhibitors, agents acting on an ATP-dependent channel of β-cells, metformin, and glucosidase inhibitors.
A method for treating Type II diabetes in an animal, comprising conjointly administering to the animal an inhibitor of dipeptidylpeptidase IV or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat Type II diabetes but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonists, prolactin inhibitors, agents acting on an ATP-dependent channel of β-cells, metformin, and glucosidase inhibitors.
A method for modifying metabolism of a peptide hormone in an animal, comprising conjointly administering to the animal one or more inhibitors of dipeptidylpeptidase IV (DPIV) or a pharmaceutically acceptable salt thereof, in a amount sufficient to modify the metabolism of a peptide hormone but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonists, prolactin inhibitors, agents acting on an ATP-dependent channel of β-cells, metformin, and glucosidase inhibitors, and the peptide hormone is selected from growth hormone-releasing factor (GHRF), vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), pituitary adenylate cyclase activating peptide (PACAP), gastric inhibitory peptide (GIP), helodermin, Peptide YY, and neuropeptide Y.
A method for modifying glucose metabolism of an animal, comprising conjointly administering to the animal, a boronyl peptidomimetic of a peptide selected from Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify glucose metabolism but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonists, prolactin inhibitors, agents acting on an ATP-dependent channel of β-cells, metformin, and glucosidase inhibitors.
A method for modifying glucose metabolism in a glucose intolerant animal, comprising conjointly administering to the animal one or more protease inhibitors which inhibit DPIV-mediated proteolysis with a Ki in the nanomolar or less range or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify glucose metabolism but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonists, prolactin inhibitors, agents acting on an ATP-dependent channel of β-cells, metformin, and glucosidase inhibitors.
A method for treating Type II diabetes in a glucose in a tolerant animal, comprising conjointly administering to the animal one or more DPIV inhibitors or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat Type II diabetes but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonists, prolactin inhibitors, agents acting on an ATP-dependent channel of β-cells, metformin, and glucosidase inhibitors.
A method for modifying metabolism of a peptide hormone in a glucose intolerant animal, comprising conjointly administering to the animal one or more inhibitors of dipeptidylpeptidase IV (DPIV) or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify the metabolism of a peptide hormone but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonists, prolactin inhibitors, agents acting on an ATP-dependent channel of β-cells, metformin, acid glucosidase inhibitors, and the inhibitor inhibits DPIV with a Ki in the nanomolar or less range, in an amount sufficient to increase the plasma half-life of the peptide hormone, which peptide hormone is selected from growth hormone-releasing factor (GHRF), vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), pituitary adenylate cyclase activating peptide (PACAP), gastric inhibitory peptide (GIP), helodermin, Peptide YY and neuropeptide Y.
A method for modifying glucose metabolism of a glucose intolerant animal, comprising conjointly administering to the animal a boronyl peptidomimetic inhibitor of a peptide selected from Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify glucose metabolism of a glucose intolerant animal but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonists, prolactin inhibitors, agents acting on an ATP-dependent channel of β-cells, metformin, and glucosidase inhibitors.
A method for treating Type II diabetes in an animal, comprising conjointly administering to the animal one or more inhibitors of a dipeptidylpeptidase or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat Type II diabetes but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonist, prolactin inhibitors, agents acting on an ATP-dependent channel of β-cells, metformin, and glucosidase inhibitor, and the inhibitor is represented by the general Formula I;
- wherein,
- A represented a 4-8 membered heterocycle including a N and a Cαcarbon;
- Z represents C or N;
- W represents CN, —CN═NR5;
- R1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group, or
- R2 is absent or represents one or more substitutions to the A, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-lower alkyl, —(CH2)m—O-lower alkenyl, —(CH2)n—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-lower alkyl, —(CH2)m—S-lower alkenyl, or —(CH2)n—S—(CH2)m—R7;
- if Z is N, then R3 represents a hydrogen;
- if Z is C, then R3 represents a hydrogen or a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O—lower alkyl, —(CH2)m—O-lower alkenyl, —(CH2)n—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)—m—S—lower alkyl, —(CH2)m—S-lower alkenyl, or —(CH2)n—S—(CH2)m—R7;
- R5 represents a hydrogen, an alkyl, an alkenyl, an alkynyl, —C(X1)(X2)X3, —(CH2)m—R7, —(CH2)n—OH, —(CH2)n—O-alkyl, —(Ch2)n—O-alkenyl, —(CH2)n—O-alkynyl, —(CH2)n—O—(CH2)m—R7, —(CH2)n—SH, —(CH2)n—S-alkyl, —(CH2)n—S-alkenyl, —(CH2)n—S-alkynyl, —(CH2)n—S—(CH2)m—R7, —C(O)C(O)NH2, or —C(O)C(O)OR′7;
- R6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-alkyl, —(CH2)m—O-alkenyl, —(CH2)m—O-alkynyl, —(CH2)m—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-alkyl, —(CH2)m—S-alkenyl, —(CH2)m—S-alkynyl, —(CH2)m—S—(CH2)m—R7;
- represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl;
- R′7 represents, for each occurrence, hydrogen, or a substituted of unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl;
- R8 and R9 each independently represent hydrogen, alkyl, alkenyl, —(CH2)m—R7, —C(═O)—alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, or —C(═O)—(CH2)m—R7,
- or R8 and R9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure;
- R50 represents O or S;
- R51 represents N3, SH, NH2, NO2 or OR′7;
- R52 represents hydrogen, a lower alkyl, an amine, OR′7, or a pharmaceutically acceptable salt, or R51 and R52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure;
- X1 represents a halogen;
- X2 and X3 each represent a hydrogen or a halogen;
- Y1 and Y2 can independently or together be OH or an alkoxyl, or taken together Y1 and Y2 are connected via a ring having from 5 to 8 atoms in the ring structure which is hydrolyzed to hydroxy groups under physiological conditions;
- m is zero or an integer in the range of 1 to 8;
- and
- n is an integer in the range of 1 to 8.
Dependencies are inferred from the claim text.