SOFT PROTEASE INHIBITORS AND PRO-SOFT FORMS THEREOF
The invention provides compounds and methods for inhibiting proteases. One aspect of the invention features pro-soft inhibitors which react with an activating protease to release an active inhibitor moiety in proximity to a target protease. In certain instances, compounds inhibit proteasomes and/or post-proline cleaving enzymes (PPCE), such as dipeptidyl peptidase IV. The compounds of the invention provide a better therapeutic index, owing in part to reduced toxicity and/or improved specificity for the targeted protease.
1 - 64 . (canceled)
65 . A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by:
or a pharmaceutical acceptable salt thereof; wherein, independently for each occurrence:
R 1 represents hydrogen, a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog;
R 9a represents hydrogen or alkyl;
R 9b represents hydrogen or alkyl;
R 10 represents the side chain of a natural or non-natural amino acid;
R 11 represents hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, or the side chain of a natural or non-natural amino acid; and
Y 1 and Y 2 , independently, are OH, or a group capable of being hydrolyzed to a hydroxyl group, or Y 1 and Y 2 are connected via a ring having from 5 to 8 atoms in the ring structure which is capable of being hydrolyzed to two hydroxyl groups.
66 . The method of claim 65 , wherein R 1 is H.
67 . The method of claim 65 , wherein R 9b is alkyl.
68 . The method of claim 65 , wherein R 9b is methyl.
69 . The method of claim 65 , wherein Y 1 and Y 2 are OH.
70 . The method of claim 69 , wherein R 9b is alkyl.
71 . The method of claim 69 , wherein R 9b is methyl.
72 . The method of claim 65 , wherein:
R 1 , R 9a and R 11 are hydrogen;
R 10 is —(CH 2 ( 2 CO 2 H;
R 9b is methyl; and
Y 1 and Y 2 are each OH.
73 . The method of claim 69 , wherein said compound is represented by:
74 . The method of claim 65 , wherein R 1 is a proline, glutamate, or alanine residue.
75 . The method of claim 65 , wherein R 1 is an alanine residue.
76 . A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
77 . The method of claim 76 , wherein the compound selected from the group consisting of:
78 . A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by
or a pharmaceutically acceptable salt thereof.
79 . The method of claim 65 , wherein the compound is a protease inhibitor.
80 . The method of claim 79 , wherein the compound inhibits dipeptidyl peptidase VIII and IX with a Ki of 100 μM or greater.
81 . A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by:
or a pharmaceutically acceptable salt thereof;
wherein, independently for each occurrence:
W represents —CN, —CH=NR 5 ,
R 1 represents a C-terminally linked peptide or peptide analog which is a substrate for an activating enzyme;
R 3 represents a hydrogen or lower alkyl;
R 4 represents hydrogen, halogen, lower alkyl, lower alkenyl, or lower alkynyl;
R 5 represents independently for each occurrence H, alkyl, alkenyl, alkynyl, —C(X 1 )(X 2 )X 3 , —(CH 2 ) m —R 7 , —(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 7 , —(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 7 , —C(O)C(O)NH 2 , or —C(O)C(O)OR′ 7 ;
R 6 represents independently for each occurrence a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;
R 7 represents independently for each occurrence hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;
R 8 represents hydrogen, —CH 3 , or —(CH 2 ) n —CH 3 ;
Y 1 and Y 2 are independently OH, or a group capable of being hydrolyzed to a hydroxyl group, or Y 1 and Y 2 are connected via a ring having from 5 to 8 atoms in the ring structure which is capable of being hydrolyzed to two hydroxyl groups;
R 10 represents hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, or the side chain of a natural or non-natural amino acid;
R 50 represents O or S;
R 51 represents N 3 , SH, 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.
82 . The method of claim 81 , wherein W is —B(Y 1 )(Y 2 ).
83 . The method of claim 81 , wherein R 4 represents hydrogen or lower alkyl.
84 . The method of claim 81 , wherein R 5 represents H or alkyl.
85 . The method of claim 81 , wherein Y 1 and Y 2 are OH.
86 . The method of claim 81 , wherein W is —B(OH) 2 .
87 . The method of claim 81 , wherein said compound is represented by:
88 . The method of claim 87 , wherein R 4 represents hydrogen or lower alkyl.
89 . The method of claim 81 , wherein R 1 is:
90 . The method of claim 81 , wherein the compound is selected from the group consisting of: