Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles

Abstract

Provided herein are peptidomimetic macrocycles and methods of using such macrocycles for the treatment of disease.

1 - 2 . (canceled) 
     
     
         3 . A peptidomimetic macrocycle comprising an amino acid sequence that is at least about 60% identical to an amino acid sequence in Tables 4, 4a, or 4b, wherein the peptidomimetic macrocycle has the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein: 
 each A, C, D, and E is independently an amino acid; 
 B is an amino acid, 
 
       
         
           
           
               
               
           
         
       
       [—NH-L 3 -CO—], [—NH-L 3 -SO 2 —], or [—NH-L 3 -];
 R 1  and R 2  are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R 1  and R 2  forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids; 
 each L and L′ is independently a macrocycle-forming linker of the formula 
 
       
         
           
           
               
               
           
         
         L 1 , L 2 , and L 3  are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 —] n , each being unsubstituted or substituted with R 5 ; 
         each R 3  is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, each being unsubstituted or substituted with R 5 ; 
         each R 4  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; 
         each K is independently O, S, SO, SO 2 , CO, CO 2 , or CONR 3 ; 
         each R 5  is independently halogen, alkyl, —OR 6 , —N(R 6 ) 2 , —SR 6 , —SOR 6 , —SO 2 R 6 , —CO 2 R 6 , a fluorescent moiety, a radioisotope, or a therapeutic agent; 
         each R 6  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope, or a therapeutic agent; 
         each R 7  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, each being unsubstituted or substituted with R 5 , or part of a cyclic structure with a D residue; 
         each R 8  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, each being unsubstituted or substituted with R 5 , or part of a cyclic structure with an E residue; 
         v and w are independently integers from 1-1000; 
         u is an integer from 1-10; 
         x, and z are independently integers from 0-10; and 
         n is an integer from 1-5. 
       
     
     
         4 - 22 . (canceled) 
     
     
         23 . The peptidomimetic macrocycle of  claim 3 , wherein each E is independently an amino acid selected from Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine). 
     
     
         24 . The peptidomimetic macrocycle of  claim 3 , wherein [D] v  comprises -Leu 1 -Thr 2 . 
     
     
         25 . The peptidomimetic macrocycle of  claim 3 , wherein w is 3-10. 
     
     
         26 . The peptidomimetic macrocycle of  claim 3  wherein w is 3-6. 
     
     
         27 . The peptidomimetic macrocycle of  claim 3  wherein w is 6-10. 
     
     
         28 . The peptidomimetic macrocycle of  claim 3  wherein w is 6. 
     
     
         29 . The peptidomimetic macrocycle of  claim 3 , wherein v is 1-10. 
     
     
         30 . The peptidomimetic macrocycle of  claim 3  wherein v is 2-10. 
     
     
         31 . The peptidomimetic macrocycle of  claim 3  wherein v is 2-5. 
     
     
         32 . (canceled) 
     
     
         33 . The peptidomimetic macrocycle of  claim 3 , wherein w is 3-1000. 
     
     
         34 . The peptidomimetic macrocycle of  claim 3 , wherein the peptidomimetic macrocycle is not a macrocycle of Table 5, Table 7, Table 7a, or Table 7b. 
     
     
         35 . The peptidomimetic macrocycle of  claim 3 , wherein each E is Ser or Ala or an analog thereof. 
     
     
         36 - 39 . (canceled) 
     
     
         40 . The peptidomimetic macrocycle of  claim 3 , wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least about 60% identical to any one of SEQ ID NOs. 456, 155, 463, 464, 468, 944, and 945. 
     
     
         41 . The peptidomimetic macrocycle of  claim 3 , wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least about 80% identical to any one of SEQ ID NOs. 456, 155, 463, 464, 468, 944, and 945. 
     
     
         42 . The peptidomimetic macrocycle of  claim 3 , wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least about 60% identical to SEQ ID NO. 945. 
     
     
         43 . The peptidomimetic macrocycle of  claim 3 , wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least about 80% identical to SEQ ID NO. 945. 
     
     
         44 . The peptidomimetic macrocycle of  claim 3 , wherein the peptidomimetic macrocycle modulates an activity of p53, MDM2, or MDMX.