PSMA binding ligand-linker conjugates and methods for using
Described herein are prostate specific membrane antigen (PSMA) binding conjugates that are useful for delivering therapeutic, diagnostic and imaging agents. Also described herein are pharmaceutical compositions containing them and methods of using the conjugates and compositions. Also described are processes for manufacture of the conjugates and the compositions containing them.
1. A conjugate comprising a ligand of PSMA (B), a linker (L), and a drug (D), wherein the ligand includes one or more of a carbon-sulfur double bond, a phosphorus-sulfur double bond, a phosphorus-sulfur single bond, a thioester, or a combination thereof, and wherein the linker is covalently bound to the drug and the linker is covalently bound to the ligand,
the linker comprises a chain of at least seven atoms, and the linker does not include a releasable linker, and
the drug comprises a radioactive isotope of a metal coordinated to a chelating group.
2. A kit comprising a sterile vial, a composition comprising the conjugate of claim 1 as a lyophilized solid, and instructions describing use of the composition for treating a patient with an inflammatory disease, wherein the vial is an amber glass vial with a rubber stopper and an aluminum tear-off seal, and the vial is stored inside a cardboard box.
3. The conjugate of claim 1 wherein B is a compound having a formula
wherein X is RYP(S)(OH)CH 2 —, RYP(S)(OH)N(R 1 )—, RP(S)(OH)CH 2 —, RP(S)(OH)N(R 1 )—, RP(S)(OH)O—, RYC(S)N(R 1 )—, RN(OH)C(S)Y, RC(S)NHY, RYP(S)(SH)CH 2 —, RYP(S)(SH)N(R 1 )—, RP(S)(SH)CH 2 —, RP(S)(SH)N(R 1 )—, RP(S)(SH)S—, RN(SH)C(S)Y—, RC(S)N(OH)Y, RS(O)Y, RSO 2 Y, RS(O)(NH)Y, or RS-alkyl; wherein Y is independently selected in each instance from —CR 1 R 2 —, —NR 3 —, —S—, and —O—, wherein R is hydrogen, alkyl, aryl, or arylalkyl, each of which may be optionally substituted; and q is 0 to 5; and
wherein R 1 , R 2 , and R 3 are each independently selected from hydrogen, C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, and aryl.
4. The conjugate of claim 3 wherein B is a compound of the formula
wherein X is RYP(S)(OH)CH 2 —, RYP(S)(OH)N(R 1 )—, RP(S)(OH)CH 2 —, RP(S)(OH)N(R 1 )—, RYC(S)N(R 1 )—, RYP(S)(SH)CH 2 —, RYP(S)(SH)N(R 1 )—, RP(S)(SH)CH 2 —, or RP(S)(SH)N(R 1 )—;
wherein Y is independently selected in each instance from —CR 1 R 2 —, —NR 3 —, —S—, and —O—;
wherein R is hydrogen, alkyl, aryl, or arylalkyl, each of which may be optionally substituted; and
q is 0 to 5.
5. The conjugate of claim 1 wherein q is 1.
6. The conjugate of claim 1 wherein Y is independently selected in each instance from —CR 1 R 2 —, and —NR 3 —.
7. The conjugate of claim 1 wherein the linker comprises a chain of at least 14 atoms.
8. The conjugate of claim 1 wherein a portion of the chain of atoms is cyclized with a divalent fragment.
9. The conjugate of claim 1 wherein the linker comprises a peptide.
10. The conjugate of claim 1 wherein the linker comprises one or more phenylalanine residues, each of which is independently optionally substituted.
11. The conjugate of claim 1 wherein the linker comprises two or more phenylalanine residues, each of which is independently optionally substituted.
12. The conjugate of claim 1 wherein the linker comprises phenylalanyl-phenylalanyl, each of which is independently optionally substituted.
13. The conjugate of claim 1 wherein the ligand is a compound selected from the group consisting of
14. The conjugate of claim 1 wherein the ligand is a fragment having a formula
wherein Q is a an amino dicarboxylic acid selected from the group consisting of aspartic acid, glutamic acid, and an analog thereof, n and m are each selected from an integer between 1 and 6, and (*) represents a point of attachment for the linker L.
15. The conjugate of claim 1 wherein the chelating group comprises a radical selected from the group consisting of
wherein * represents a point of attachment to the rest of the conjugate.
16. The conjugate of claim 1 wherein the chelating group comprises a radical of
wherein each of R 1 , R 2 , and R 3 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, heteroalkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, and wherein one of R 1 , R 2 , and R 3 comprises a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur, and is the point of attachment for the linker L.
17. A pharmaceutical composition comprising a therapeutically effective amount of the conjugate or the pharmaceutically acceptable salt thereof of claim 1 , and a component selected from the group consisting of carriers, diluents, and excipients, and combinations thereof.
18. A method for treating a disease involving a pathogenic cell population expressing PSMA, the method comprising administering to a patient in need of relief from the disease a therapeutically effective amount of the conjugate of claim 1 , optionally with a component selected from the group consisting of carriers, diluents, excipients, and combinations thereof.
19. The conjugate of claim 1 , wherein the linker does not include a disulfide bond.
20. The conjugate of claim 15 , wherein the linker does not include a disulfide bond.