Peptidomimetic Inhibitors of Post-Proline Cleaving Enzymes
The present invention relates to 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 of the present invention 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 compounds of the present invention 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:
wherein
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 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;
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 does 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 Cα 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;
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 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 6 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 any of claims 1 - 4 , 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 or 2 , 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 or 2 , wherein R 4a and R 4b each represent hydrogen, and R 4c represents a small hydrophobic group.
9 . The inhibitor of claim 1 , 2 or 5 , wherein R 4a and R 4b each represent hydrogen, and R 4c 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 any of claims 1 , 3 or 9 , wherein R 2 is absent, or represents —OH.
12 . The inhibitor of any of claims 1 - 6 , 9 or 11 , wherein R 3a a hydrogen and R 3b is absent.
13 . The inhibitor of any of claims 1 - 12 , 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 any of claims 1 - 12 , wherein R 1 is an amino acid residue or a peptidyl moiety which is a substrate for a protease.
16 . The inhibitor of any of the foregoing claims, wherein the protease inhibitor inhibits DPIV with a Ki of 50 nm or less.
17 . The inhibitor of any of the foregoing claims, which inhibitor is orally active.
18 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a protease inhibitor of any of claims 1 - 17 , or a pharmaceutically acceptable salt or prodrug thereof.
19 . Use of an inhibitor of any of claims 1 - 17 in the manufacture of a medicament for inhibiting a post-proline cleaving enzyme in vivo.
20 . The use of claim 19 , wherein the inhibitor increases plasma concentrations of a peptide hormone selected from glucagon like peptide, NPY, PPY, secretin, GLP-1, GLP-2, and GIP.
21 . Use of an inhibitor of any of claims 1 - 17 in the manufacture of a medicament for regulating glucose metabolism.
22 . The use of claim 21 , for regulating glucose metabolism of a patient suffering from Type II diabetes, insulin resistance, glucose intolerance, hyperglycemia, hypoglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia.
23 . A method for inhibiting the proteolytic activity of a post-proline cleaving enzyme, comprising contacting the enzyme with a protease inhibitor of any of claims 1 - 17 .
24 . A packaged pharmaceutical comprising: a preparation of any of the protease inhibitor of claims 1 - 17 ; 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 any of the protease inhibitor of claims 1 - 17 ; 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 M1 receptor antagonist, a prolactin inhibitor, agents acting on the ATP-dependent potassium channel of n-cells, metformin, and/or glucosidase inhibitors.