Smart pro-drugs of serine protease inhibitors
The present invention relates to prodrugs of protease inhibitors, such as inhibitors of the proteosome, DPP 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 as 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-inactivate by, e.g., intramolecular-cyclization or cis-trans isomerization.
1. A compound represented by formula (II), or a pharmaceutically acceptable salt thereof:
wherein
B represents a boron atom;
the R′ 3 —N(H) bond is cleaved by Fibroblast Activating Factor (FAP) to release R′ 3 and a dipeptidyl proteosome inhibitor;
Y 1 and Y 2 are OH;
R 1 is H or lower alkyl;
R 2 is H, lower alkyl, cycloalkyl, or aralkyl;
R 3 is H or lower alkyl;
R′ 3 is a dipeptidyl moiety or tripeptidyl moiety consisting of α-amino acids selected from the group consisting of natural α-amino acids and non-natural α-amino acids, wherein the amino terminus of said dipeptidyl moiety or tripeptidyl moiety is optionally substituted with an amino-terminal protecting group, and the C-terminal α-amino acid of said dipeptidyl moiety or tripeptidyl moiety is proline; and
the dipeptidyl proteosome inhibitor, when released from the compound by cleavage by FAP, inhibits the proteolytic activity of a proteosome with a Ki of 100 nM or less and undergoes reversible cyclization-dependent inactivation over time.
2. The compound of claim 1 , wherein at least one amino acid of R′ 3 is a non-natural α-amino acid.
3. The compound of claim 1 , wherein at least one amino acid of R′ 3 is a non-natural α-D-amino acid.
4. The compound of claim 1 , wherein the amino terminus of R′ 3 is substituted with an amino-terminal protecting group.
5. The compound of claim 4 , wherein the amino-terminal protecting group is an acyl group.
6. The compound of claim 5 , wherein the acyl group is selected from the group consisting of formyl, dansyl, acetyl, benzoyl, trifluoroacetyl, succinyl and methoxysuccinyl.
7. A pharmaceutical composition, comprising a compound of claim 1 ; and a pharmaceutically acceptable carrier.
8. A packaged pharmaceutical, comprising a formulation comprising a compound of claim 1 and a pharmaceutically acceptable excipient; and instructions (written and/or pictorial) describing the recommended dosage and/or administration of the formulation to a patient.
9. The compound of claim 1 , wherein R 1 is lower alkyl.
10. The compound of claim 1 , wherein R 1 is isobutyl.
11. The compound of claim 1 , wherein R 3 is H.
12. The compound of claim 1 , wherein R 1 is isobutyl; and R 3 is H.
13. The compound of claim 1 , wherein R′ 3 is a dipeptidyl moiety or tripeptidyl moiety consisting of α-amino acids selected from the group consisting of natural α-amino acids.
14. A pharmaceutical composition, comprising a compound of claim 13 ; and a pharmaceutically acceptable carrier.
15. A packaged pharmaceutical, comprising a formulation, comprising a compound of claim 13 , and a pharmaceutically acceptable excipient; and instructions (written and/or pictorial) describing the recommended dosage and/or administration of the formulation to a patient.