Phenylalanine-based LAT1 inhibitors and uses thereof
Phenylalanine-based inhibitors of the Large Amino Acid Transporter 1 (LAT1) are disclosed. The compounds are useful in modulating the transcellular transport of substrates of LAT1 such as large neutral amino acids. The compounds are useful in immunomodulation therapies.
1. A compound having the structure of Formula (3):
or a pharmaceutically acceptable salt thereof, wherein,
R 6 is selected from —COOH, —COOR a , —COR a , and —CON(R b ) 2 , wherein,
R a is C 1-4 alkyl; and
each R b is independently selected from hydrogen, —OH, C 1-4 alkyl, and C 1-4 alkoxy;
R 7 is selected from hydrogen and methyl;
R 8 is selected from hydrogen, halogen, C 1-3 alkyl, and C 1-3 alkoxy;
R 9 is selected from —S(O) 2 —NR— and —NR—S(O) 2 —, wherein R is selected from hydrogen and methyl;
R 10 is selected from C 6-10 aryl, substituted C 6-10 aryl, C 5-6 cycloalkyl, and biphenyl; and
each substituent is independently selected from halogen, phenyl, —N(—R) 2 , C 1-4 alkoxy, and C 1-4 alkyl, wherein each R is independently selected from hydrogen and methyl.
2. The compound of claim 1 , wherein R 6 is —COOH.
3. The compound of claim 1 , wherein R 7 is hydrogen.
4. The compound of claim 1 , wherein R 8 is methyl.
5. The compound of claim 1 , wherein R 9 is —S(O) 2 —NR—.
6. The compound of claim 1 , wherein R 9 is —NR—S(O) 2 —.
7. The compound of claim 1 , wherein R 9 is —S(O) 2 —NH—.
8. The compound of claim 1 , wherein R 9 is —NH—S(O) 2 —.
9. The compound of claim 1 , wherein R 10 is phenyl.
10. The compound of claim 1 , wherein R 10 is substituted phenyl.
11. The compound of claim 10 , wherein the substituted phenyl is 4-substituted phenyl.
12. The compound of claim 10 , wherein the substituted phenyl is 3-substituted phenyl.
13. The compound of claim 10 , wherein the substituent is selected from Cl, Br, methoxy, and benzyl.
14. The compound of claim 1 , wherein R 10 is naphthyl.
15. The compound of claim 1 , wherein R 10 is substituted naphthyl.
16. The compound of claim 15 , wherein the substituted naphthyl is 5-substituted naphthyl.
17. The compound of claim 15 , wherein the substituent is —N(R) 2 .
18. The compound of claim 15 , wherein the substituent is —N(—CH 3 ) 2 .
19. The compound of claim 1 , wherein R 10 is biphenyl.
20. The compound of claim 1 , wherein R 10 is cyclohexyl.
21. The compound of claim 1 , wherein
R 6 is —COOH;
R 7 is hydrogen;
R 8 is methyl; and
R 9 is —S(O) 2 —NH—.
22. The compound of claim 1 , wherein
R 6 is —COOH;
R 7 is hydrogen;
R 8 is methyl; and
R 9 is —NH—S(O) 2 —.
23. The compound of claim 1 , wherein the compound is selected from:
(S)-2-amino-3-(5-((5-(dimethylamino)naphthalene)-1-sulfonamido)-2-methylphenyl)propanoic acid (2);
(S)-2-amino-3-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)propanoic acid (3);
(S)-2-amino-3-(2-methyl-5-((4-methylphenyl)sulfonamido)phenyl)propanoic acid (7);
(S)-2-amino-3-(2-methyl-5-(phenylsulfonamido)phenyl)propanoic acid (10);
(S)-2-amino-3-(5-((5-(dimethylamino)naphthalene)-1-sulfonamido)-2-isopropylphenyl)propanoic acid (21);
(S)-2-amino-3-(5-((3-bromophenyl)sulfonamido)-2-methylphenyl)propanoic acid (29);
(S)-2-amino-3-(5-(N-benzylsulfamoyl)-2-methylphenyl)propanoic acid (30);
(S)-2-amino-3-(2-methyl-5-(N-phenylsulfamoyl)phenyl)propanoic acid hydrochloride (35);
(S)-3-(5-([1,1′-biphenyl]-3-sulfonamido)-2-methylphenyl)-2-aminopropanoic acid (38);
(S)-2-amino-3-(2-methyl-5-(N-(naphthalen-1-yl)sulfamoyl)phenyl)propanoic acid (39);
(S)-3-(5-(N-([1,1′-biphenyl]-4-yl)sulfamoyl)-2-methylphenyl)-2-aminopropanoic acid (40);
(S)-2-amino-3-(5-((3,5-dichlorophenyl)sulfonamido)-2-methylphenyl)propanoic acid (43);
(S)-2-amino-3-(5-(N-(4-methoxyphenyl)sulfamoyl)-2-methylphenyl)propanoic acid (44);
(S)-2-amino-3-(5-(N-(5-(dimethylamino)naphthalen-1-yl)sulfamoyl)-2-methylphenyl)propanoic acid (49);
(S)-2-amino-3-(5-(N-(4-chlorophenyl)sulfamoyl)-2-methylphenyl)propanoic acid (52);
(S)-2-amino-3-(5-(N-cyclohexylsulfamoyl)-2-methylphenyl)propanoic acid (53);
(S)-2-amino-3-(5-((benzylthio)methyl)-2-methylphenyl)propanoic acid (55);
(S)-2-amino-3-(5-(benzylsulfonyl)-2-methylphenyl)propanoic acid (65);
(S)-2-amino-3-(5-(N-(3-bromophenyl)sulfamoyl)-2-methylphenyl)propanoic acid (76);
(S)-2-amino-3-(5-(N-(4-bromophenyl)sulfamoyl)-2-methylphenyl)propanoic acid (77);
(S)-2-amino-3-(3-(N-(4-chlorophenyl)sulfamoyl)phenyl)propanoic acid (79);
tert-butyl (S)-2-amino-3-(5-(N-(4-chlorophenyl)sulfamoyl)-2-methylphenyl)propanoate (82);
(S)-2-amino-3-(5-(N-(4-chlorophenyl)-N-methylsulfamoyl)-2-methylphenyl)propanoic acid (84);
(S)-2-amino-3-(5-(N-(4-chlorophenyl)sulfamoyl)-2-isopropylphenyl)propanoic acid (86); and
(S)-2-amino-3-(5-((4-(tert-butyl)phenyl)sulfonamido)-2-methylphenyl)propanoic acid (87);
or a pharmaceutically acceptable salt of any of the foregoing.
24. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable vehicle.
25. A method of treating an organ transplant rejection, an acute graft-vs-host-disease, or a chronic graft-vs-host-disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
26. A method of treating a disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the disease is selected from alopecia, pemphigus, psoriasis, scleroderma, vitiligo, dermatitis, asthma, fibrosis, rheumatoid arthritis, lupus, Crohn's disease, ulcerative colitis, and Celiac disease.
27. A method of treating an organ transplant rejection, an acute graft-vs-host-disease, or a chronic graft-vs-host-disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 24 .
28. A method of treating a disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 24 , wherein the disease is selected from alopecia, pemphigus, psoriasis, scleroderma, vitiligo, dermatitis, asthma, fibrosis, rheumatoid arthritis, lupus, Crohn's disease, ulcerative colitis, and Celiac disease.