PEPTIDOMIMETIC INHIBITORS OF POST-PROLINE CLEAVING ENZYMES
Disclosed are inhibitors of post-proline cleavage enzymes, such as inhibitors of dipeptidyl peptidase IV, as well as pharmaceutical compositions thereof, and methods for using such inhibitors. In particular, the inhibitors are improved over those in the prior art by selection of particular classes of side chains in the P1 and/or P2 position of the inhibitor. The inhibitors can have a better therapeutic index, owing in part to reduced toxicity and/or improved specificity for the targeted protease.
1 . A protease inhibitor represented by Formula I:
A represents a 3-8 membered heterocycle including the N and the Cα carbon;
W represents a functional group which reacts with an active site residue of the targeted protease to form a covalent adduct;
R 1 represents a hydrogen, a C-terminally linked amino acid or peptide or analog thereof, or amino protecting group;
R 2 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, —(CH 2 ) m —R 6 , —(CH 2 ) m —OH, —(CH 2 ) m —O-lower alkyl, —(CH 2 ) m —O-lower alkenyl, —(CH 2 ) n —O—(CH 2 ) m —R 6 , —(CH 2 ) m —SH, —(CH 2 ) m —S-lower alkyl, —(CH 2 ) m —S-lower alkenyl, —(CH 2 ) n —S—(CH 2 ) m —R 6 ;
R 3a represents a hydrogen or a substituent which does not conjugate the electron pair of the nitrogen from which it pends;
R 3b is absent, or represents a substituent which does not conjugate the electron pair of the nitrogen from which it pends, such as a lower alkyl;
R 4a and R 4b each independently represent a hydrogen, lower alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl, carboxyl, carboxamide, carbonyl, or cyano, with the caveat that either both or neither of R4a and R4b are hydrogen;
R 4c represents a halogen, an amine, an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl, carboxyl, carboxamide, carbonyl, or cyano;
R 6 represents, independently for each occurrence, an aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle moiety;
z is zero or an integer in the range of 1 to 3; 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.
2 . A protease inhibitor represented by Formula III:
wherein
R represents hydrogen, a halogen, or a branched or unbranched C1-C6 alkyl;
W represents a functional group which reacts with an active site residue of the targeted protease to form a covalent adduct;
R 1 represents a hydrogen, a C-terminally linked amino acid or peptide or analog thereof, or amino protecting group;
R 3a represents a hydrogen or a substituent which not conjugate the electron pair of the nitrogen from which it pends, such as a lower alkyl;
R 3b is absent, or represents a substituent which does not conjugate the electron pair of the nitrogen from which it pends, such as a lower alkyl;
R 4a and R 4b each independently represent a hydrogen, lower alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl, carboxyl, carboxamide, carbonyl, or cyano, with the caveat that either both or neither of R 4a and R 4b are hydrogen;
R 4c represents a halogen, an amine, an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl, carboxyl, carboxamide, carbonyl, or cyano; and
z is zero or an integer in the range of 1 to 3.
3 . A protease inhibitor represented by Formula IV: wherein A represents a 3-8 membered heterocycle including the N and the Ca carbon; B represents a C3-C8 ring, or C7-C14 fused bicyclic or tricyclic ring system; W represents a functional group which reacts with an active site residue of the targeted protease to form a covalent adduct; R1 represents a hydrogen, a C-terminally linked amino acid or peptide or analog thereof, or amino protecting group, 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-R6, —(CH2) m-OH, —(CH2) m-0-lower alkyl, —(CH2) m-0-lower alkenyl, —(CH2) n-O—(CH2) m-R6, —(CH2) m-SH, —(CH2) m-S-lower alkyl, —(CH2) m-S-lower alkenyl, —(CH2) ri-S—(CH2) m-R6; R3b is absent, or represents a substituent which does not conjugate the electron pair of the nitrogen from which it pends, such as a lower alkyl; R6 represents, independently for each occurrence, an aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle moiety; 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.
4 . A protease inhibitor represented by Formula VI:
wherein
B represents a C3-C8 ring, or C7-C14 fused bicyclic or tricyclic ring system;
W represents a functional group which reacts with an active site residue of the targeted protease to form a covalent adduct;
R represents hydrogen, a halogen, or a branched or unbranched C1-C6 alkyl;
R 1 represents a hydrogen, a C-terminally linked amino acid or peptide or analog thereof, or amino protecting group; and
R 3b is absent, or represents a substituent which does not conjugate the electron pair of the nitrogen from which it pends, such as a lower alkyl.
5 . The inhibitor of claim 1 , wherein W represents —CN, —CH═NR 5 ,
wherein,
Y 1 and Y 2 each independently represent —OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y 1 and Y 2 are connected via a ring having from 5 to 8 atoms in the ring structure;
R 5 represents H, an alkyl, an alkenyl, an alkynyl, —C(X 1 )(X 2 )X 3 , —(CH 2 )m-R 6 , —(CH 2 )n-OH, —(CH 2 )n-O-alkyl, —(CH 2 )n-O-alkenyl, —(CH 2 )n-O-alkynyl, —(CH 2 )n-O—(CH 2 )m-R 6 , —(CH 2 )n-SH, —(CH 2 )n-S-alkyl, —(CH 2 )n-S-alkenyl, —(CH 2 )n-S-alkynyl, —(CH 2 )n-S—(CH 2 )m-R 6 , —C(O)C(O)NH 2 , —C(O)C(O)OR 7 ;
R 6 represents, independently for each occurrence, an aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle moiety;
R 7 represents, independently for each occurrence, hydrogen, or an alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle moiety;
R 50 represents O or S;
R 51 represents N 3 , SH 2 , NH 2 , NO 2 or —OR 7 ;
R 52 represents hydrogen, a lower alkyl, an amine, —OR 7 , or a pharmaceutically acceptable salt, or R 51 and R 52 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
X 1 represents a halogen;
X 2 and X 3 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.
6 . The inhibitor of claim 1 , wherein R 4a , R 4b and R 4c each independently represent a small hydrophobic group.
7 . The inhibitor or claim 6 , wherein R 4a , R 4b and R 4c , are independently selected from the group consisting of halogens, lower alkyls, lower alkenyls, and lower alkynyls.
8 . The inhibitor of claim 1 , wherein R 4a and R 4b each represent hydrogen, and R 4c represents a small hydrophobic group.
9 . The inhibitor of claim 1 , wherein R 4a and R 4b each represent hydrogen, and represents a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
10 . The inhibitor of claim 9 , wherein R 4c represents a C3-C8 cycloalkyl.
11 . The inhibitor of claim 1 , wherein R 2 is absent, or represents —OH.
12 . The inhibitor of claim 1 , wherein R 3a a hydrogen and R 3b is absent.
13 . The inhibitor of any of claim 1 , wherein W represents:
wherein,
Y 1 and Y 2 each independently represent —OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y 1 and Y 2 are connected via a ring having from 5 to 8 atoms in the ring structure;
R 5 represents H, an alkyl, an alkenyl, an alkynyl, —C(X 1 )(X 2 )X 3 , —(CH 2 )m-R 6 , —(CH 2 )n-OH, —(CH 2 )n-O-alkyl, —(CH 2 )n-O-alkenyl, —(CH 2 )n-O-alkynyl, —(CH 2 )n-O—(CH 2 )m-R 6 , —(CH 2 )n-SH, —(CH 2 )n-S-alkyl, —(CH 2 )n-S-alkenyl, —(CH 2 )n-S-alkynyl, —(CH 2 )n-S—(CH 2 )m-R 6 , —C(O)C(O)NH 2 , —C(O)C(O)OR 7 ;
R 6 represents, independently for each occurrence, an aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle moiety;
R 7 represents, independently for each occurrence, hydrogen, or an alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle moiety;
X 1 represents a halogen;
X 2 and X 3 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 inhibitor of claim 13 , wherein R 5 is a hydrogen or —C(X 1 )(X 2 )X 3 , wherein X 1 is a fluorine, and X 2 and X 3 , if halogens, are also fluorine.
15 . The inhibitor of claim 1 , wherein R 1 is an amino acid residue or a peptidyl moiety which is a substrate for a protease.
16 - 17 . (canceled)
18 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a protease inhibitor of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof.
19 - 22 . (canceled)
23 . A method for inhibiting the proteolytic activity of a post-proline cleaving enzyme, comprising contacting the enzyme with a protease inhibitor of claim 1 .
24 . A packaged pharmaceutical comprising: a preparation of the protease inhibitor of claim 1 ; a pharmaceutically acceptable carrier; and instructions, written and/or pictorial, describing the use of the preparation for inhibiting a post-proline cleaving enzyme in vivo.
25 . A packaged pharmaceutical comprising: a preparation of the protease inhibitor of claim 1 ; a pharmaceutically acceptable carrier; and instructions, written and/or pictorial, describing the use of the preparation for regulating glucose metabolism.
26 . The packaged pharmaceutical of claim 25 , wherein the protease inhibitor is co-formulated with, or co-packaged with, insulin and/or an insulinotropic agent.
27 . The packaged pharmaceutical of claim 25 , wherein the protease inhibitor is co-formulated with, or co-packaged with, an MI receptor antagonist, a prolactin inhibitor, agents acting on the ATP-dependent potassium channel of p-cells, metformin, and/or glucosidase inhibitors.