Inhibitors of Fibroblast Activation Protein Alpha
Disclosed are peptide-based compounds that include boronic acid or cyano functionality, which efficiently and selectively inhibit fibroblast activation protein alpha. Among other therapeutic utilities, the peptide-based compounds may be useful for the treatment of cancer.
1 . A compound having a structure of formula (I)
wherein
L is absent or represents —XC(O)—;
R 1 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 acyl, C 1-6 aralkyl, C 1-6 aracyl, C 1-6 heteroaracyl, carbocyclyl, aryl, and ArSO 2 —;
R 2 is selected from the group consisting of H and C 1-6 alkyl, or R 1 and R 2 together are phthaloyl, thereby forming a ring;
R 3 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 thioalkyl, and C 1-6 aralkyl;
W is selected from the group consisting of B(Y 1 )(Y 2 ) and CN;
Y 1 and Y 2 are independently OH or a group that is hydrolyzable to a boronic acid, or together with the boron atom to which they are attached form a 5- to 8-membered ring that is hydrolyzable hydrolyzable to a boronic acid; and
X is selected from the group consisting of O and NH.
2 . The compound of claim 1 , wherein R 3 is selected from the group consisting of H and C 1-6 alkyl.
3 . The compound of claim 2 , wherein W is B(Y 1 )(Y 2 ); and R 3 is H.
4 . The compound of claim 3 , wherein Y 1 and Y 2 are both OH.
5 . The compound of claim 2 , wherein L is absent.
6 . The compound of claim 5 , wherein R 1 and R 2 together are phthaloyl, thereby forming a ring.
7 . The compound of claim 5 , wherein R 1 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 acyl, C 1-6 aralkyl, C 1-6 aracyl, C 1-6 heteroaracyl, carbocyclyl, aryl, and ArSO 2 —.
8 . The compound of claim 7 , wherein R 1 is H.
9 . The compound of claim 7 , wherein R 1 is C 1-6 alkyl.
10 . The compound of claim 9 , wherein R 1 is selected from the group consisting of methyl, ethyl, isopropyl, and tert-butyl.
11 . The compound of claim 7 , wherein R 1 is C 1-6 acyl.
12 . The compound of claim 11 , wherein R 1 is selected from the group consisting of acetyl and pivaloyl.
13 . The compound of claim 7 , wherein R 1 is C 1-6 aralkyl.
14 . The compound of claim 13 , wherein R 1 is phenylmethyl.
15 . The compound of claim 7 , wherein R 1 is C 1-6 aracyl.
16 . The compound of claim 15 , wherein R 1 is selected from the group consisting of 2-phenylethylcarbonyl, phenylmethylcarbonyl, (1-naphthyl)carbonyl, (2-naphthy)carbonyl, and (4-sulfamoylphenyl)carbonyl.
17 . The compound of claim 7 , wherein R 1 is C 1-6 heteroaracyl.
18 . The compound of claim 17 , wherein R 1 is pyrazyl.
19 . The compound of claim 7 , wherein R 1 is carbocyclyl.
20 . The compound of claim 19 , wherein R 1 is selected from the group consisting of cyclohexyl and adamantyl.
21 . The compound of claim 7 , wherein R 1 is aryl.
22 . The compound of claim 21 , wherein R 1 is phenyl.
23 . The compound of claim 7 , wherein R 1 is ArSO 2 —.
24 . The compound of claim 23 , wherein R 1 is phenylsulfonyl.
25 . The compound of claim 4 , wherein L is —XC(O)—.
26 . The compound of claim 25 , wherein X is O.
27 . The compound of claim 26 , wherein R 1 is C 1-6 aralkyl.
28 . The compound of claim 27 , wherein R 1 is phenylmethyl.
29 . The compound of claim 25 , wherein X is NH.
30 . The compound of claim 29 , wherein R 1 is selected from the group consisting of aryl and C 1-6 aralkyl.
31 . The compound of claim 30 , wherein R 1 is aryl.
32 . The compound of claim 31 , wherein R 1 is phenyl.
33 . The compound of claim 30 , wherein R 1 is C 1-6 aralkyl.
34 . The compound of claim 33 , wherein R 1 is phenylmethyl.
35 . A compound having a structure of formula (II)
wherein
R 1 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 acyl, C 1-6 aralkyl, C 1-6 aracyl, C 1-6 heteroaracyl, and carbocyclyl;
R 2 is selected from the group consisting of H and C 1-6 alkyl;
R 3 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 thioalkyl, and C 1-6 aralkyl;
R 4 is selected from the group consisting of H and C 1-6 alkyl, or R 3 and R 4 together are C 1-6 alkyl, thereby forming a ring;
R 5 is selected from H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 thioalkyl, and C 1-6 aralkyl, or R 4 and R 5 together are C 1-6 alkyl-S;
W is selected from H, B(Y 1 )(Y 2 ), and CN; and
Y 1 and Y 2 are independently OH or a group that is hydrolyzable to a boronic acid, or together with the boron atom to which they are attached form a 5- to 8-membered ring that is hydrolyzable to a boronic acid;
with the proviso that when W is H, R 4 and R 5 together are C 1-6 alkyl-S—C 1-6 alkyl.
36 . The compound of claim 35 , wherein R 1 is selected from the group consisting of C 1-6 acyl and C 1-6 aracyl; R 3 and W are H; and R 4 and R 5 together are C 1-6 alkyl-S—C 1-6 alkyl, thereby forming a ring.
37 . The compound of claim 36 , wherein R 4 and R 5 together are C 2 alkyl-S—C 1 alkyl, thereby forming a five-membered ring.
38 . The compound of claim 35 , wherein R 1 is selected from the group consisting of C 1-6 acyl and C 1-6 aracyl; and R 3 and R 4 together are C 1-6 alkyl, thereby forming a ring.
39 . The compound of claim 38 , wherein R 3 and R 4 together are C 3 alkyl, thereby forming a five-membered ring.
40 . The compound of claim 35 , wherein R 3 and R 5 are selected from the group consisting of H and C 1-6 alkyl.
41 . The compound of claim 40 , wherein W is B(Y 1 )(Y 2 ).
42 . The compound of claim 41 , wherein Y 1 and Y 2 are both OH.
43 . The compound of claim 42 , wherein R 1 is selected from the group consisting of C 1-6 acyl and C 1-6 aracyl; R 2 and R 4 are H; and R 3 and R 5 are C 1-6 alkyl.
44 . The compound of claim 43 , wherein R 1 is C 1-6 acyl.
45 . The compound of claim 44 , wherein R 1 is acetyl.
46 . The compound of claim 43 , wherein R 1 is C 1-6 aracyl.
47 . The compound of claim 46 , wherein R 1 is selected from the group consisting of phenylcarbonyl and (1-naphthyl)carbonyl.
48 . A method for treating cancer, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 .
49 . The method of claim 48 , wherein the cancer is selected from human epithelial cancer and soft tissue carcinoma.
50 . The method of claim 49 , wherein the cancer is human epithelial cancer selected from the group consisting of breast cancer, non-small-cell lung cancer, and colorectal cancer.
51 . A pharmaceutical composition, comprising a compound of claim 1 ; and a pharmaceutically acceptable diluent or carrier.
52 - 54 . (canceled)
55 . A method for treating cancer, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 35 .
56 . The method of claim 55 , wherein the cancer is selected from human epithelial cancer and soft tissue carcinoma.
57 . The method of claim 56 , wherein the cancer is human epithelial cancer selected from the group consisting of breast cancer, non-small-cell lung cancer, and colorectal cancer.
58 . A pharmaceutical composition, comprising a compound of claim 35 ; and a pharmaceutically acceptable diluent or carrier.