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. A compound represented by:
or a pharmaceutically acceptable salt thereof;
wherein
A represents a 4-8 membered heterocycle including the N and the Cα carbon;
R 1 represents a C-terminally linked amino acid residue or amino acid analog R 6 ; wherein the bond between R 1 and N is a thioxamide bond;
R 2 is absent or represents one or more substitutions to the ring A, each of which is independently a halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl, carboxyl, ester, formate, ketone, thiocarbonyl, thioester, thioacetate, thioformate, amino, acylamino, amido, nitro, sulfate, sulfonate, sulfonamido, —(CH 2 ) m —R 7 , —(CH 2 ) m —OH, —(CH 2 ) m —O-lower alkyl, —(CH 2 ) m —O-lower alkenyl, —(CH 2 ) n —O—(CH 2 ) m —R 7 , —(CH 2 ) m —SH, —(CH 2 ) m —S-lower alkyl, —(CH 2 ) m —S-lower alkenyl, or —(CH 2 ) n —S—(CH 2 ) m —R 7 , azido, cyano, isocyanato, thiocyanato, isothiocyanato, cyanato,
or
R 3 represents hydrogen or a halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl, thiocarbonyl, amino, acylamino, amido, nitro, sulfate, sulfonate, a sulfonamido, —(CH 2 ) m —R 7 , —(CH 2 ) m —OH, —(CH 2 ) m —O-lower alkyl, —(CH 2 ) m —O-lower alkenyl, —(CH 2 ) n —O—(CH 2 ) m —R 7 , (CH 2 ) m —SH, —(CH 2 ) m —S-lower alkyl, —(CH 2 ) m —S-lower alkenyl, or —(CH 2 ) n —S—(CH 2 ) m —R 7 , azido, cyano, isocyanato, thiocyanato, isothiocyanato, cyanato,
or
R 6 represents hydrogen, a halogen, alkyl, alkenyl, alkynyl, aryl, —(CH 2 ) m —R 7 , —(CH 2 ) m —OH, —(CH 2 ) m —O-alkyl, —(CH 2 ) m —O-alkenyl, —(CH 2 ) m —O-alkynyl, —(CH 2 ) m —O—(CH 2 ) m —R 7 , —(CH 2 ) m —SH, —(CH 2 ) m —S-alkyl, —(CH 2 ) m —S-alkenyl, —(CH 2 ) m —S-alkynyl, —(CH 2 ) m —S—(CH 2 ) m —R 7 ,
R 7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;
R 8 represents hydrogen, —CH 3 , or —(CH 2 ) n —CH 3 ;
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;
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. The compound of claim 1 , wherein Y 1 and Y 2 , independently, are OH.
3. The compound of claim 2 , wherein said compound is represented by:
4. The compound of claim 1 , wherein R 2 is absent, or represents lower alkyl or halogen.
5. The compound of claim 1 , wherein R 3 is hydrogen.
6. The compound of claim 1 , wherein the Cα carbon exists substantially in the R configuration.
7. The compound of claim 1 , wherein the Cα carbon exists substantially in the S configuration.
8. The compound of claim 1 , wherein the Cα carbon exists in a racemic mixture of R and S configurations.
9. The compound of claim 1 , wherein Y 1 and Y 2 are OH.
10. The compound of claim 1 , wherein R 1 is a proline, glutamate, or alanine residue.
11. The compound of claim 1 , wherein R 1 is an alanine residue.
12. A compound selected from the group consisting of:
and enantiomers, diastereomers and salts thereof.
13. The compound of claim 1 , wherein the compound is a protease inhibitor.
14. The compound of claim 13 , wherein the compound inhibits dipeptidyl peptidase IV with a Ki of 50 nM or less.
15. The compound of claim 14 , wherein the compound inhibits dipeptidyl peptidase VIII and IX with a Ki of 100 microM or greater.
16. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier; and a compound of claim 1 .