Method of regulating glucose metabolism, and reagents related thereto

A method for treating Type II diabetes, comprising administering to an animal a composition including one or more inhibitors of dipeptidylpeptidase IV (DPIV) represented by Formula I in an amount sufficient to treat Type II diabetes but not sufficient to suppress the immune system of the animal:

• wherein
• A represents a 4-8 membered heterocycle including the N and a Cα carbon;
• Z represents C or N;
• W represents —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, 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), —R7, —(CH2)n—OH, —(CH2)n—O-alkyl, —(CH2), —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;
• 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;
• Y1 and Y2 can independently or together be a group capable of being hydrolyzed to a hydroxyl group, or cyclic derivatives where Y1 and Y2 are connected via a 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.