Method of regulating glucose metabolism, and reagents related thereto

A method for treating Type II diabetes in an animal in need thereof, comprising conjointly administering to the animal a composition including 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 inhibitor is represented by the general Formula I:

• 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, 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 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)2—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 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.