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US 10,245,248 B2Granted
FAP-activated therapeutic agents, and uses related thereto
AssigneeBach Biosciences, LLC
InventorsWilliam W. Bachovchin, Hung-sen Lai, David G. Sanford, Sarah E. Poplawski, Wengen Wu
Life of this patent
Estimating the term…
Abstract
Disclosed are prodrugs of therapeutic or imaging agents, which prodrugs are selectively cleaved by fibroblast activating protein (FAP) to release the agents. Upon cleavage by FAP of the FAP substrate, the prodrug releases the agent in its active form or in a form that is readily metabolized to its active form. Pharmaceutical compositions comprising the prodrugs, as well as methods of using the prodrugs to treat a disorder characterized by FAP upregulation are also disclosed.
Claims11
A prodrug represented by the general formula
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 represents (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkyl-C(O)—(C1-C10)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C10)alkyl, aryl, aryl(C1-C10)alkyl, heteroaryl, or heteroaryl(C1-C10)alkyl, wherein any R1 is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, carboxylate, cyano, amino, nitro, and thio (—SH);
- or —C(═X)R1 represents an N-terminally blocked alpha amino acid residue and X is O;
- R2 represents H or a (C1-C6)alkyl;
- R3 represents a (C1-C6)alkyl;
- R4 is absent or represents one, two or three substituents, each independently selected from a (C1-C6)alkyl, —OH, —NH2, or halogen;
- X represents O or S;
- Cyt′, or Cyt′L-NH, represents a cytotoxic compound or cytostatic compound, less a hydrogen atom;
- and
- L represents a 4- to 8-membered ring which is part of the cytotoxic compound or cytostatic compound and is recognized by FAP as a P′1 residue;
- or L is a self-immolative linker which is metabolized after FAP cleavage to release Cyt′,
- wherein the prodrug is selectively converted to the cytotoxic compound or cytostatic compound by FAP+ stromal cells.
9 more elements
A prodrug represented by the general formula
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 represents a heteroaryl polycyclic moiety;
- R2 represents H or a (C1-C6)alkyl;
- Cyt′ or Cyt′L-NH, represents a cytotoxic compound or cytostatic compound, less a hydrogen atom;
- and
- L represents a 4- to 8-membered ring which is part of the cytotoxic compound or cytostatic compound and is recognized by FAP as a P′1 residue;
- or L is a self-immolative linker which is metabolized after FAP cleavage to release Cyt′,
- wherein the prodrug is selectively converted to the cytotoxic compound or cytostatic compound by FAP+ stromal cells.
5 more elements
A prodrug represented by the general formula
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 represents a heteroaryl moiety;
- R2 represents H or a (C1-C6)alkyl;
- Cyt′ or Cyt′-L-NH, represents a cytotoxic compound or cytostatic compound, less a hydrogen atom;
- and
- L represents a 4- to 8-membered ring which is part of the cytotoxic compound or cytostatic compound and is recognized by FAP as a P′1 residue;
- or L is a self-immolative linker which is metabolized after FAP cleavage to release Cyt′,
- wherein the prodrug is selectively converted to the cytotoxic compound or cytostatic compound by FAP+ stromal cells.
5 more elements
A prodrug represented by the general formula
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 represents (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkyl-C(O)—(C1-C10)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C10)alkyl, aryl, aryl(C1-C10)alkyl, heteroaryl, or heteroaryl(C1-C10)alkyl, wherein any R1 is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, carboxylate, cyano, amino, nitro, and thio (—SH);
- or —C(═X)R1 represents an N-terminally blocked alpha amino acid residue and X is O;
- R2 represents H or a (C1-C6)alkyl;
- R3 represents H or a (C1-C6)alkyl;
- R4 is absent or represents one, two or three substituents, each independently selected from a (C1-C6)alkyl, —OH, —NH2, or halogen;
- X represents O or S;
- Cyt′ represents a cytotoxic compound or cytostatic compound, less a hydrogen atom;
- and
- L is a self-immolative linker comprising a heterocycle,
- wherein the prodrug is selectively converted to the cytotoxic compound or cytostatic compound by FAP+ stromal cells.
8 more elements
Dependencies are inferred from the claim text.