Conformationally constrained peptide mimetics
View Patent ↗Conformationally constrained peptide mimetics in which a hydrogen bond interaction is replaced with a covalent hydrogen bond mimic are provided. Also provided are various methods of making these peptide mimetics.
1. A compound of Formula I
wherein
X is —CR a R b —;
Y is —CR c R d —;
R a , R b , R c , and Rd are independently —H or a substituted or unsubstituted alkyl or aralkyl group;
R 1 at each occurrence is independently —H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl group; or, R 1 together with the carbon to which it is attached and the adjacent nitrogen, forms a substituted or unsubstituted pyrrolidine, oxazolidine, thiazolidine, imidazolidine, or piperidine ring;
R 2 and R 3 are independently —H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group; or R 2 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolidine, oxazolidine, thiazolidine, imidazolidine, or piperidine ring;
R 4 is —H, a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group, —C(O)—R 1 , or a —C(O)—CHR 1 —NH—R 6 group; or R 4 and R 2 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolidine, oxazolidine, thiazolidine, imidazolidine, or piperidine ring;
R 5 is a —H, a substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl or a heteroaralkyl group, —NH 2 , —NH—C(O)—R 7 , or a —NH—CHR 1 —C(O)—R 7 group;
R 6 is —H, a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group, —C(O)R 10 , —C(O)OR 10 , —[C(O)—CHR 1 —NH] m —R 10 , —[C(O)—CHR 1 —NH] m —C(O)R 10 , or —[C(O)—CHR 1 —NH] m —C(O)R 10 ;
R 7 is —H, a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group, —NR 10 R 10 , —OR 10 or —[NH—CH R 10 —C(O)] m —;
R 10 at each occurrence is independently —H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group;
m at each occurrence is independently an integer from 1 to 20; and
n is an integer from 1 to 20.
2. The compound of claim 1 wherein R a is a substituted or unsubstituted C 1-6 alkyl group, R c is a substituted or unsubstituted C 1-6 alkyl group, or both R a and R c are substituted or unsubstituted C 1-6 alkyl groups.
3. The compound of claim 1 wherein X is —CH 2 —, Y is —CH 2 —, or each of X and Y is —CH 2 —.
4. The compound of claim 1 wherein R 1 and R 2 are independently —H, benzyl optionally substituted with one or more OH or halogen, imidazolylmethyl, indolylmethyl, or a C 1-6 alkyl group optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —OH, —O—PG 1 , —SH, —S—PG 2 , —NH 2 , —NH-PG 3 , —C(O)OH, —C(O)O—PG 4 , —C(O)NH 2 , or —NHC(NH)NH 2 ; and wherein
PG 1 is a hydroxyl protecting group;
PG 2 is a thiol protecting group;
PG 3 is an amino protecting group; and
PG 4 is a carboxyl protecting group.
5. The compound of claim 1 wherein R 2 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolidine ring.
6. The compound of claim 1 wherein R 4 is a —(C(O)—CHR 1 —NH—R 6 group.
7. The compound of claim 1 wherein R 6 is —H, —C(O)R 10 , —C(O)OR 10 , —[C(O)—CHR 1 —NH] m —R 10 , or —[C(O)—CHR 1 —NH] m —C(O)R 10 .
8. The compound of claim 1 wherein R 5 is a —NH—CHR 1 —C(O)—R 7 group.
9. The compound of claim 1 wherein R 7 is —OR 10 , —NR 10 R 10 , or —[NH—CHR 1 —C(O)] m —.
10. A compound of Formula I
wherein
X is —CR a R b —;
Y is —CR c R d —;
R a , R b , R c , and Rd are independently —H or a substituted or unsubstituted alkyl or aralkyl group;
R 1 at each occurrence is independently —H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl group; or, R 1 together with the carbon to which it is attached and the adjacent nitrogen, forms a substituted or unsubstituted pyrrolidine, oxazolidine, thiazolidine, imidazolidine, or piperidine ring;
R 2 is —H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl; heterocyclylalkyl, heteroaryl or heteroaralkyl group; or R 2 and R 4 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolidine, oxazolidine, thiazolidine, imidazolidine, or piperdine ring;
R 3 is a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl,
aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group,
R 4 is —H, a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group, —C(O)—R 1 , or a —C(O)—CHR 1 —NH—R 6 group; or R 4 and R 2 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolidine, oxazolidine, thiazolidine, imidazolidine, or piperidine ring;
R 5 is a —H, a substituted or unsubstituted alkyl, aryl, aralkyl, heteroaryl or a heteroaralkyl group, —NH 2 , —NH—C(O)—R 7 , or a —NH—CHR 1 —C(O)—R 7 group;
R 6 is —H, a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group, —C(O)R 10 , —C(O)OR 10 , —[C(O)—CHR 1 —NH] m —R 10 , —[C(O)—CHR 1 —NH] m —C(O)R 10 , or —[C(O)—CHR 1 —NH] m —C(O)R 10 ;
R 7 is —H, a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group, —NR 10 R 10 , —OR 10 , or —[NH—CH R 10 —C(O)] m ;
R 10 at each occurrence is independently —H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group;
m at each occurrence is independently an integer from 1 to 20; and
n is an integer from 1 to 20.
11. The compound of claim 1 , wherein n is 1, 2, or 3.
12. The compound of claim 3 , wherein n is 1, 2, or 3.
13. The compound of claim 10 , wherein n is 1, 2, or 3.