Dimeric small molecule potentiators of apoptosis
View Patent ↗Caspase activity and apoptosis are promoted using active, dimeric Smac peptide mimetics of the general formula M1-L-M2, wherein moieties M1 and M2 are monomeric Smac mimetics and L is a covalent linker. Target cancerous or inflammatory cells are contacted with an effective amount of an active, dimeric Smac mimetic, and a resultant increase in apoptosis of the target cells is detected. The contacting step may be effected by administering to a pharmaceutical composition comprising a therapeutically effective amount of The compoundic mimetic, wherein the individual may be subject to concurrent or antecedent radiation or chemotherapy for treatment of a neoproliferative pathology.
1. A pro-apoptotic Smac (second mitochondria-derived activator of caspases) peptide mimetic dimeric compound of the general formula M1-L-M2, wherein moieties M1 and M2 are monomeric Smac mimetics and L is a linker covalently linking M1 and M2 in the active dimeric compound, wherein M1-L-M2 is of formula II,
wherein:
R1 and R1′ are selected from hydrogen, optionally substituted methyl, and hydroxyl;
R2 and R2′ are selected from optionally substituted methyl and optionally substituted ethyl;
R3 and R3′ are selected from CH2, NH, O and S;
R4 and R4′ are selected from CH and N;
R5-R8, and R5′-R8′ are selected from hydrogen, optionally hetero-, optionally substituted alkyl, optionally hetero-, optionally substituted alkenyl, optionally hetero-, optionally substituted alkynyl, optionally hetero-, optionally substituted aryl, wherein optionally either R6 and R7 as well as R6′ and R7′ or R7 and R8 as well as R7′ and R8′ are connected in 5- to 8-membered rings; and
L is a contiguous chain of between 2 and 200 atoms, having a MW between 20 D and 2 KD that can incorporate substitution, heteroatoms, unsaturation and cyclic aromatic and heteroaromatic portions,
or a pharmaceutically-acceptable salt thereof.
2. The compound of claim 1 wherein:
R1 and R1′ are selected from hydrogen and methyl;
R2 and R2′ are selected from methyl and ethyl;
R3 and R3′ are NH;
R4 and R4′ are CH;
R5 and R5′ are methyl, ethyl, propyl or butyl; and
R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings,
or a pharmaceutically-acceptable salt thereof.
3. The compound of claim 1 wherein:
R1 and R1′ are selected from hydrogen and methyl;
R2 and R2′ are selected from methyl and ethyl;
R3 and R3′ are NH;
R4 and R4′ are CH;
R5 and R5′ are methyl, ethyl, propyl or butyl;
R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings;
R8 is H; and
L covalently links R5, R6 or R7, with R5′, R6′ or R7′, respectively,
or a pharmaceutically-acceptable salt thereof.
4. The compound of claim 1 wherein:
R1 and R1′ are selected from hydrogen and methyl;
R2 and R2′ are selected from methyl and ethyl;
R3 and R3′ are NH;
R4 and R4′ are CH;
R5 and R5′ are methyl, ethyl, propyl or butyl;
R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings;
R8 is H; and
L covalently links R6 or R7, with R6′ or R7′, respectively,
or a pharmaceutically-acceptable salt thereof.
5. The compound of claim 1 wherein:
R1 and R1′ are selected from hydrogen and methyl;
R2 and R2′ are selected from methyl and ethyl;
R3 and R3′ are NH;
R4 and R4′ are CH;
R5 and R5′ are methyl, ethyl, propyl or butyl;
R6 and R6 are optionally substituted alkyl;
R7 and R7 are optionally substituted methyl;
R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings;
R8 is H; and
L covalently links R6 or R7, with R6′ or R7′, respectively,
or a pharmaceutically-acceptable salt thereof.
6. The compound of claim 1 wherein:
R1 and R1′ are selected from hydrogen and methyl;
R2 and R2′ are selected from methyl and ethyl;
R3 and R3′ are NH;
R4 and R4′ are CH;
R5 and R5′ are methyl, ethyl, propyl or butyl;
R6 and R6 are optionally substituted ethyl;
R7 and R7 are optionally substituted methyl;
R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings;
R8 is H; and
L covalently links R6 or R7, with R6′ or R7′, respectively,
or a pharmaceutically-acceptable salt thereof.
7. The compound of claim 1 wherein:
R1 and R1′ are selected from hydrogen and methyl;
R2 and R2′ are selected from methyl and ethyl;
R3 and R3′ are NH;
R4 and R4′ are CH;
R5 and R5′ are methyl, ethyl, propyl or butyl;
R6 and R6 are substituted ethyl;
R7 and R7 are substituted methyl;
R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings;
R8 is H; and
L covalently links R6 or R7, with R6′ or R7′, respectively,
or a pharmaceutically-acceptable salt thereof.
8. The compound of claim 1 wherein:
R1 and R1′ are selected from hydrogen and methyl;
R2 and R2′ are selected from methyl and ethyl;
R3 and R3′ are NH;
R4 and R4′ are CH;
R5 and R5′ are methyl, ethyl, propyl or butyl;
R6 and R6 are substituted ethyl;
R7 and R7 are substituted methyl;
R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings;
R8 is H; and
L covalently links R6, with R6′,
or a pharmaceutically-acceptable salt thereof.
9. The compound of claim 1 wherein:
R1 and R1′ are selected from hydrogen and methyl;
R2 and R2′ are selected from methyl and ethyl;
R3 and R3′ are NH;
R4 and R4′ are CH;
R5 and R5′ are methyl, ethyl, propyl or butyl;
R6 and R6 are linker-substituted ethyl;
R7 and R7 are hydroxyl-substituted methyl;
R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings;
R8 is H; and
L covalently links R6, with R6′,
or a pharmaceutically-acceptable salt thereof.
10. The compound of claim 1 wherein:
R1 and R1′ is methyl;
R2 and R2′ are selected from methyl and ethyl;
R3 and R3′ are NH;
R4 and R4′ are CH;
R5 and R5′ are methyl, ethyl, propyl or butyl;
R6 and R6 are linker-substituted ethyl;
R7 and R7 are hydroxyl-substituted methyl;
R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings;
R8 is H; and
L covalently links R6, with R6′,
or a pharmaceutically-acceptable salt thereof.
11. The compound of claim 1 wherein:
R1 and R1′ is methyl;
R2 and R2′ are methyl;
R3 and R3′ are NH;
R4 and R4′ are CH;
R5 and R5′ are methyl, ethyl, propyl or butyl;
R6 and R6 are linker-substituted ethyl;
R7 and R7 are hydroxyl-substituted methyl;
R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings;
R8 is H; and
L covalently links R6, with R6′,
or a pharmaceutically-acceptable salt thereof.
12. The compound of claim 1 wherein:
R1 and R1′ is methyl;
R2 and R2′ are methyl;
R3 and R3′ are NH;
R4 and R4′ are CH;
R5 and R5′ are ethyl;
R6 and R6 are linker-substituted ethyl;
R7 and R7 are hydroxyl-substituted methyl;
R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings;
R8 is H; and
L covalently links R6, with R6′,
or a pharmaceutically-acceptable salt thereof.
13. The compound of claim 1 , wherein L is a contiguous chain of between 4 and 100 atoms, and between 40D and 1 kD.
14. The compound of claim 1 wherein L incorporates heteroaromatic portions.
15. The compound of claim 3 wherein L incorporates heteroaromatic portions.
16. The compound of claim 11 wherein L incorporates heteroaromatic portions.
17. The compound of claim 1 , wherein the dimer is symmetrical.
18. The compound of claim 3 , wherein the dimer is symmetrical.
19. The compound of claim 11 , wherein the dimer is symmetrical.
20. The compound of claim 14 , wherein the dimer is symmetrical.
21. The compound of claim 15 , wherein the dimer is symmetrical.
22. The compound of claim 16 , wherein the dimer is symmetrical.
23. The pharmaceutical composition comprising a unit dosage of the compound of claim 1 and a pharmaceutically acceptable excipient.
24. The pharmaceutical composition comprising a unit dosage of the compound of claim 3 and a pharmaceutically acceptable excipient.
25. The pharmaceutical composition comprising a unit dosage of the compound of claim 11 and a pharmaceutically acceptable excipient.
26. The pharmaceutical composition comprising a unit dosage of the compound of claim 16 and a pharmaceutically acceptable excipient.
27. The pharmaceutical composition comprising a unit dosage of the compound of claim 22 and a pharmaceutically acceptable excipient.