Smart pro-drugs of serine protease inhibitors
The present invention relates to prodrugs of protease inhibitors, such as inhibitors of proteosome, DPOP IV, FAPα and the like. These “pro-inhibitors” are activated, i.e., cleaved by an “activated protease” to release an active inhibitor moiety in proximity to a “target protease”. The identity of activating protease and target protease can be the same (such pro-inhibitors being referred to as “Target-Activated Smart Protease Inhibitors” or “TASPI”) or different (e.g., “Target-Directed Smart Protease Inhibitors” or “TDSPI”). After activation of the pro-inhibitor, the active inhibitor moiety can self-inactive by, e.g., intramolecular-cyclization or cis-trans isomerization.
1. A pro-inhibitor represented by the formula (I) or a pharmaceutically acceptable salt thereof:
A-G (I)
wherein
A represents Chg-Pro;
A and G are covalently linked by a bond that is cleaved by the activating protease; and
G represents Val-boroPro;
wherein, the inhibitor moiety G, when cleaved from A by the activating serine protease, undergoes reversible conformation-dependent inactivation and/or inhibits the target protease with a Ki of 100 nM or less.
2. The pro-inhibitor of claim 1 , wherein the target protease is a serine protease.
3. The pro-inhibitor of claim 1 , wherein the activating protease is a serine protease.
4. The pro-inhibitor of claim 1 , wherein the activating protease is a metalloprotease.
5. The pro-inhibitor of claim 1 , wherein the activating protease is a cysteine protease.
6. The pro-inhibitor of claim 1 , wherein the K i for the inactive conformer is at least 5 times greater than the K i for the active conformer of the inhibitor moiety G.
7. The pro-inhibitor of claim 1 , wherein the therapeutic index for the pro-inhibitor is at least 2 times greater than the therapeutic index for the inhibitor moiety G administered alone.
8. The pro-inhibitor of claim 1 , provided in a pharmaceutical preparation that is substantially pyrogen-free.
9. The pro-inhibitor of claim 8 , wherein a single administration of the pharmaceutical preparation can produce a therapeutically effective amount of the inhibitor moiety G for a period of at least 4 hours.
10. The pro-inhibitor of claim 1 , wherein G undergoes reversible pH-dependent inactivation.
11. The pro-inhibitor of claim 1 , wherein the amino terminus of A is blocked with an amino-terminal protecting group.
12. The pro-inhibitor of claim 1 , wherein the target protease is a post-prolyl cleaving protease.
13. The pro-inhibitor of claim 12 , wherein the target protease is selected from the group consisting of DPP IV, DPP II, Prolyl oligopeptidase (PO), Fibroblast Activating Protein (FAP), and prolyl carboxypeptidase.
14. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier; and a pro-inhibitor of claim 1 or a pharmaceutically acceptable salt thereof.
15. A packaged pharmaceutical comprising one or more pro-inhibitors of claim 1 , formulated in a pharmaceutically acceptable excipient, in association with instructions (written and/or pictorial) describing the recommended dosage and/or administration of the formulation to a patient.