Method of regulating glucose metabolism, and reagents related thereto

• US 6,890,898 B2
• Filed: 07/03/2002
• Issued: 05/10/2005
• Est. Priority Date: 02/02/1998
• Status: Expired due to Term

• Current Assignee: 1149336 Ontario Inc., Arisaph Pharmaceuticals, Inc., New England Medical Center Hospitals, Inc.
• Original Assignee: 1149336 Ontario Inc., New England Medical Center Hospitals, Inc., Trustees of Tufts College
• Inventors: Bachovchin, William W., Plaut, Andrew G., Drucker, Daniel
• Primary Examiner(s): RUSSEL, JEFFREY E
• Application Number:
  US10/190,267
• Publication Number:
  US 20030153509A1
• Time in Patent Office: 1,042 Days
• Field of Search: 514/2, 514/18, 514/19, 514/119, 514/423, 514/626, 530/330, 530/331
• US Class Current: 514/5.9
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 31/702 Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
• CPC Class Codes: A61K 38/005 Enzyme inhibitors protease inhibitors A61K38/55
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 38/55 Protease inhibitors
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 : of the pancreatic hormones
• CPC Class Codes: A61P 5/50 : for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid

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.

Claims

1. 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.

2. 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.

3. The method of claim 1 or 2, wherein administering the inhibitor reduces one or more of insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia.

4. The method of claim 1 or 2, Wherein the inhibitor bas an EC₅₀ for modification of glucose metabolism which is at least one order of magnitude less than its EC₅₀ for immunosuppression.

5. The method of claim 1 or 2, wherein the inhibitor has an EC₅₀ for inhibition of glucose tolerance in the nanomolar or less range.

6. The method of claim 1 or 2, wherein the inhibitor has an EC₅₀ for immunosuppression in the μ

M or greater range.

7. The method of claim 1 or 2, wherein the inhibitor has a K_i for DPIV inhibition of 10 nM or less.

8. The method of claim 1 or 2, wherein the inhibitor has a K_i for DPIV inhibition of 1.0 nM or less.

9. The method of claim 1 or 2, wherein the inhibitor is peptidomimetic of a peptide selected from Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala.

10. The method of claim 1 or 2, wherein the inhibitor has a molecular weight less than 7500 amu.

11. The method of claim 1 or 2, wherein the inhibitor is administered orally.

12. The method of claim 1 or 2, wherein the inhibitor is represented by the general formula:

wherein

A represents a 4-8 membered heterocycle including the N and a Cα

carbon;

Z represents C or N;

W represents CN, —

CH═

NR₅, a functional group which reacts with an active site residue of the targeted protease, or

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 ring A, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynl, 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)_mOH, —

(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, R₃ represents hydrogen, if Z is C, R₃ represents 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 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, or —

(CH₂)_m—

S—

(CH₂)_m—

R₇,

R₇ represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;

R₇ represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl;

R₈ and R₉ each independently represent hydrogen, alkyl, alknyl, —

(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 a group capable of being to a hydroxyl group, including cyclic derivatives where Y₁ and Y₂ are connected via a ring having from 5 to 8 atoms in the ring structure;

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.

13. The method of claim 12, wherein

W represents CN, —

CH═

NR₅,

R₅ represents H, 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;

R₇ represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl;

R₇ represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; and

Y₁ and Y₂ can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y₁ and Y₂ are connected via a ring having from 5 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;

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.

14. The method of claim 13, wherein the ring A is represented by the formula

wherein n is an integer of 1 or 2.

15. The method of claim 13, wherein W represents

16. The method of claim 13, wherein R₁ represents

wherein

R₃₆ is a small hydrophobic group and R₃₈ is hydrogen, or, R₃₆ and R₃₈ together form a 4-7 membered heterocycle including the N and the Cα

carbon, as defined for above; and

R₄₀ represents a C-terminally linked amino acid residue or amino acid analog, or C-terminally linked peptide or peptide analog, or an amino-protecting group.

17. The method of claim 13, wherein R₂ is absent, or represents a small hydrophobic group.

18. The method of claim 13, wherein R₃ is a hydrogen, or a small hydrophobic group.

19. The method of claim 12, wherein R₅ is a hydrogen, or a halogenated lower alkyl.

20. The method of claim 13, wherein X₁ is a fluorine, and X₂ and X₃, if halogens, are fluorine.

21. The method of claim 12, wherein the inhibitor is represented by the general formula:

wherein

R₁ represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or

R₆ represents 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,

R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle;

R₈ and R₉ each independently represent hydrogen, alkyl, alkenyl, —

(CH₂)_m—

R₇, —

C(═

O)alkyl, —

C(═

O)-alkenyl, —

C(═

O)-alkynyl, —

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;

R₁₁ and R₁₂ each independently represent hydrogen, an alkyl, or a pharmaceutically acceptable salt, or R₁₁ and R₁₂ taken together with the O-B-O atoms to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure;

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.

22. The method of claim 12, wherein the inhibitor is represented by the general formula:

wherein

R₁ represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or

R₆ represents 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, —

(C)_m—

SH, —

(CH₂)_m—

S-alkyl, —

(CH₂)_m—

S-alkenyl, —

(CH₂)_m—

S-alkynyl, —

(CH₂)_m—

S—

(CH₂)_m—

R₇,

R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle;

R₈ and R₉ each independently represent hydrogen, alkyl, alkenyl, —

(CH₂)_m—

R₇, —

C(═

O)-alkyl, —

C(═

O)-alkenyl, -C(═

O)-alkynyl, —

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;

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.

23. The method of claim 1 or 2, wherein the inhibitor is represented by the general formula:

wherein

R₁ represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or

R₆ represents 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,

R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle;

R₈ and R₉ each independently represent hydrogen, alkyl, alkenyl, —

(CH₂)_m—

R₇, —

C(═

O)-alkyl, —

C(═

O)-alkenyl, —

C(═

O)-alkynyl, —

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;

X₁, X₂ and X₃ each represent a hydrogen or a halogen;

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.

24. The method of claim 13, wherein the inhibitor is represented by the general formula:

wherein

A represents a 4-8 membered heterocycle including an N and a Cα

carbon;

W represents CN, —

CH═

NR₅,

R₂ is absent or represents one or more substitutions to the ring 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;

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;

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 or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl;

R₃₂ is a small hydrophobic group;

R₃₀ 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;

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 a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y₁ and Y₂ are connected via a ring having from 5 to 8 atoms in the ring structure;

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.

25. 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.

26. 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.

27. The method of claim 26, wherein the boronyl peptidomimetic is represented in the general formula:

wherein

each A independently represents a 4-8 membered heterocycle including the N and a Cα

carbon;

R₂ is absent or represents one or more substitutions to the ring 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 akyl, —

(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;

R₃ represents 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;

R₆ represents 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 or —

(CH₂)_m—

S—

(CH₂)_m—

R₇;

R₇ represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;

R₃₀ represents a C-terminally linked amino acid residue or amino acid analog, or C-terminally linked peptide or peptide analog, or an amino-protecting group, or

R₃₂ represents a small hydrophobic group;

R₆₂ represents lower alkyl or halogen;

Y₁ and Y₂ can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y₁ and Y₂ are connected via a ring having from 5 to 8 atoms in the ring structure;

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.

28. The method of claim 27, wherein administering the boronyl peptidomimetic reduces one or more of insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia.

29. The method of claim 27, wherein the boronyl peptidomimetic has an EC₅₀ for modification of glucose metabolism which is at least one order of magnitude less than its EC₅₀ for immunosuppression.

30. The method of claim 27, wherein the boronyl peptidomimetic has an EC₅₀ for inhibition of glucose tolerance in the nanomolar or less range.

31. The method of claim 27, wherein the boronyl peptidomimetic has an EC₅₀ for inhibition of glucose tolerance of 10 nM or less.

32. The method of claim 27, wherein the boronyl peptidomimetic has an EC₅₀ for immunosuppression in the μ

M or greater range.

33. The method of claim 27, wherein the boronyl peptidomimetic is administered orally.

34. 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 K_i 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.

35. 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.

36. 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 K_i 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.

37. 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.

38. The method of claim 34, 35, 36 or 37 wherein administering the inhibitor reduces one or more of insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia.

39. The method of claim 34, 35, 36 or 37 wherein the inhibitor has an EC₅₀ for modification of glucose metabolism which is at least one order of magnitude less than its EC₅₀ for immunosuppression.

40. The method of claim 34, 35, 36 or 37 wherein the inhibitor has an EC₅₀ for inhibition of glucose tolerance in the nanomolar or less range.

41. The method of claim 34, 35, 36 or 37 wherein the inhibitor has an EC₅₀ for immunosuppression in the μ

M or greater range.

42. The method of any of claim 34, 35, 36 or 37 wherein the inhibitor has a K_i for DPIV inhibition of 10 nM or less.

43. The method of claim 34, 35, 36 or 37 wherein the inhibitor is peptidomimetic of a peptide selected from Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala.

44. The method of claim 34, 35, 36 or 37 wherein the inhibitor has a molecular weight less than 7500 amu.

45. The method of claim 34, 35, 36 or 37 wherein the inhibitor is administered orally.

46. The method of claim 34, 35, 36 or 37 wherein the inhibitor is represented by the general Formula VII:

wherein,

A represents a 4-8 membered heterocycle including a N and a Cα

carbon;

Z represents C or N;

W represents CN, —

CH═

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,

R₂ is absent or represents one or mare substitutions to the ring 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, R₃ represents a hydrogen;

if Z is C, 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, —

(C₂)_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,

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 or 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 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;

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.

47. The method of claim 46, wherein W represents CN, —

CH═

NR₅,

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—

alkenyl, —

(CH₂)_n—

S-alkynyl, —

(CH₂)_n—

S—

(CH₂)_m—

R₇, —

C(O)C(O)NH₂, or —

C(O)C(O)OR′

₇;

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 or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl;

Y₁ and Y₂ can independently or together be hydroxyl, 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;

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; and

X₂ and X₃ each represent a hydrogen or a halogen.

48. The method of claim 46, wherein the ring A is represented by the formula

wherein,

n is an integer of 1 or 2.

49. The method of claim 46, wherein W represents

50. The method of claim 46, wherein R₁ represents

R₃₆ represents a small hydrophobic group and R₃₈ is hydrogen, or, R₃₆ and R₃₈ together form a 4-7 membered heterocycle including the N and the Cα

carbon, as defined for A above; and

R₄₀ 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.

51. The method of claim 46, wherein R₂ is absent, or represents a small hydrophobic group.

52. The method of claim 46, wherein R₃ is a hydrogen, or a small hydrophobic group.

53. The method of claim 46, wherein R₅ is a hydrogen, or a halogenated lower alkyl.

54. The method of claim 46, wherein X₁ is a fluorine, and X₂ and X₃, if halogens, are fluorine.

55. The method of claim 46, wherein the inhibitor is represented by the general formula (VIII):

wherein,

R₁ represents a C-terminally linked amino acid residue or amino acid analog, or C-terminally linked peptide or peptide analog,

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,

R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle;

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;

R₁₁ and R₁₂ each independently represent hydrogen, an alkyl, or a pharmaceutically acceptable salt, or R₁₁ and R₁₂ taken together with the O—

B—

O atoms to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure;

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.

56. The method of claim 46, wherein the inhibitor is represented by the general Formula IX:

wherein

R₁ represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog,

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)_mS-alkyl, —

(CH₂)_m—

S-alkenyl, —

(CH₂)_m—

S-alkynyl, —

(CH₂)_m—

S—

(CH₂)_m—

R₇,

R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle;

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;

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.

57. The method of claim 46, wherein the inhibitor is represented by the general formula:

wherein,

R₁ represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog,

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)_mR₇, —

(CH₂)_m—

SH, —

(CH₂)_m—

S-alkyl, —

(CH₂)_m—

S-alkenyl, —

(CH₂)_m—

S-alkynyl, —

(CH₂)_m—

S—

(CH₂)_m—

R₇,

R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle;

R₈ and R₉ each independently represent hydrogen, alkyl, alkenyl, —

(CH₂)_m—

R₇, —

C(═

O)-alkyl, —

C(═

O)-alkenyl, —

C(═

O)-alkynyl, —

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;

X₁, X₂ and X₃ each represent a hydrogen or a halogen;

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.

58. The method of claim 46, wherein the inhibitor is represented by the general Formula Xa or Xb:

wherein,

A represents a 4-8 membered heterocycle including a N and a Cα

carbon;

W represents —

CN, —

CH═

NR₅,

R₅ represents a hydrogen, an alkyl, an alkenyl, an alkynyl, —

(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;

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 or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl;

R₃₂ is a small hydrophobic group;

R₃₀ 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;

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 a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y₁ and Y₂ are connected via a ring having from 5 to 8 atoms in the ring structure;

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.

59. 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 Cα

carbon;

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—

(CH_2)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.

60. The method of claim 59, wherein the ring A is represented by the formula

wherein,

n is an integer of 1 or 2.

61. The method of claim 59, wherein W

represents.

62. The method of claim 59, wherein R₁ represents

R₃₆ represents a small hydrophobic group and R₃₈ is hydrogen, or, R₃₆ and R₃₈ together form a 4-7 membered heterocycle including the N and a Cα

carbon; and

R₄₀ 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.

63. The method of claim 59, wherein R₂ is absent, or represents a small hydrophobic group.

64. The method of claim 59, wherein R₃ is a hydrogen, or a small hydrophobic group.

65. The method of claim 59, wherein R₅ is a hydrogen, or a halogenated lower alkyl.

66. The method of claim 59, wherein X₁ is a fluorine, and X₂ and X₃, if halogens, are fluorine.

67. The method of claim 59, wherein the inhibitor is represented by the general Formula (II):

wherein,

R₁ represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog,

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,

R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle;

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;

R₁₁ and R₁₂ each independently represent hydrogen, an alkyl, or a pharmaceutically acceptable salt, or R₁₁ and R₁₂ taken together with the O—

B—

O atoms to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure;

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.

68. The method of claim 59, wherein the inhibitor is represented by the general Formula III:

wherein,

R₁ represents a C-terminally linked amino acid residue or amino acid analog, or C-terminally linked peptide or peptide analog,

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,

R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle;

R₈ and R₉ each independently represent hydrogen, alkyl, alkenyl, —

(CH₂)_m—

R₇, —

(═

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;

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.

69. The method of claim 59, wherein the inhibitor is represented by the general formula:

wherein,

R₁ represents a C-terminally linked amino acid residue or amino acid analog, or C-terminally linked peptide or peptide analog, or an amino protecting group, or

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,

R₇ represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle;

R₈ and R₉ each independently represent hydrogen, alkyl, alkenyl, —

(CH₂)_m—

R₇, —

C(═

O)-alkyl, —

C(═

O)-alkenyl, —

C(═

O)-alkynyl, —

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;

X₁, X₂ and X₃ each represent a hydrogen or a halogen;

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.

70. The method of claim 59, wherein the inhibitor is represented by the general Formula IVa or IVb:

wherein,

A represents a 4-8 membered heterocycle including an N and a Cα

carbon;

W represents CN, —

CH═

NR₅,

R₂ is absent or represents one or more substitutions to the ring 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;

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;

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 or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl;

R₃₀ 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;

R₃₂ is a small hydrophobic group;

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;

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.

71. The method of claim 70, wherein the ring A is represented by the formula

wherein,

n is 1 or 2.

72. The method of claim 70, wherein R₂ is absent, or represents a small hydrophobic group.

73. The method of claim 70, wherein R₃ is a hydrogen, or a small hydrophobic group.

74. The method of claim 59, wherein the inhibitor is peptidomimetic of a peptide selected from Pro-Pro and Ala-Pro.

75. The method of claim 59, wherein the inhibitor has an EC₅₀ for immunosuppression in the μ

M or greater range.

76. The method of claim 59, wherein the inhibitor is administered orally.

77. The method of claim 59, wherein administering the inhibitor reduces one or more of insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia.

78. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, wherein said conjointly administering is achieved by simultaneous dosing of the individual components.

79. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, wherein said conjointly administering is achieved by sequential dosing of the individual components.

80. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, wherein said conjointly administering is achieved by separate dosing of the individual components.

81. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, wherein said conjointly administering is achieved by doping the individual components in the same composition.

82. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, wherein the M1 receptor antagonist is selected from quaternary amines, tertiary amines, tricyclic amines, pirenzepine, methyl scopolamine, benztropine, hexahydro-sila-difenidol hydrochloride, ( /−

)-3-quinuclidinyl xanthene-9-carboxylate hemioxalate, and atropine.

83. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, wherein said prolactin inhibitor is selected from d2 dopamine agonists, prolactin-inhibiting ergo alkaloids, and prolactin-inhibiting dopamine agonists.

84. A method of claim 80, wherein said prolactin-inhibiting dopamine agonist is selected from 2-bromo-alpha-ergocriptine, 6-methyl-8-beta-carbobenzyloxyaminomethyl-10-alpha-ergoline, 8-acylaminoergolines, 6-methyl-8-alpha-(N-acyl)amino-9-ergoline, 6-methyl-8-alpha-(N-phenylacetyl)amino-9-ergoline, ergocornine, 9,10-dihydroergocornine, D-2-halo-6-alkyl-8-substituted ergolines, D-2-bromo-6-methyl-8-cyanomethylergoline, carbidopa, benserazide, other dopadecarboxylase inhibitor L-dopa, and dopamine.

85. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, wherein said agent acting on an ATP-dependent channel of β

-cells is selected from glibenclamide, glipizide, gliclazide, and AG-EE 623 ZW.

86. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, wherein said glucosidase inhibitor is acarbose.

87. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, comprising conjointly administering to the animal a composition comprising a pharmaceutically acceptable carrier, an inhibitor of dipeptidylpeptidase IV, or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agent, 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.

88. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, wherein the other therapeutic agent is metformin.