Arginase inhibitors and methods of use thereof
Disclosed are compounds of formula (Ia) or a pharmaceutically acceptable salt thereof pharmaceutical compositions comprising compounds of formula (Ia) and methods of using the same for treating cancer or a respiratory inflammatory disease and inhibiting arginase: wherein R 1 is —NHR 1a ; R 1a is —H or —C(O)CH(R 1b )NHR 1c ; and R 1b is selected from —H, —(C 1 -C 4 ) alkyl and CH 2 OR 1d and R 1c is —H; or R 1b and R 1c , together with the atom to which they are attached, form a 5-membered heterocyclic ring; and R 1d is H or —CH 3 .
1. A method of treating a respiratory inflammatory disease associated with Arginase 1 or Arginase 2 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof:
wherein
R 2 is —OH or —NHR 2a :
R 2a is —H or —C(O)CH(R 2b )NH 2 ; and
R 2b is —CH 3 or —CH(CH 3 ) 2 .
2. The method of claim 1 , wherein the compound is represented by formula (III), or a pharmaceutically acceptable salt thereof:
wherein R 3 is —CH 3 or —CH(CH 3 ) 2 .
3. A method of treating a respiratory inflammatory disease associated with Arginase 1 or Arginase 2 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (IIb), or a pharmaceutically acceptable salt thereof:
wherein
R 2 is —OH or —NHR 2a ;
R 2a is —H or —C(O)CH(R 2b )NH 2 ; and
R 2b is —CH 3 or —CH(CH 3 ) 2 .
4. The method of claim 3 , wherein the compound is represented by formula (IIIb), or a pharmaceutically acceptable salt thereof:
wherein R 3 is —CH 3 or —CH(CH 3 ) 2 .
5. The method of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 , wherein the compound has the following structure:
or a pharmaceutically acceptable salt thereof.
7. The method of claim 1 , wherein the compound has the following structure:
8. The method of claim 1 , wherein the compound has the following structure:
or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 , wherein the compound has the following structure:
10. The method of claim 3 , wherein the compound has the following structure:
or a pharmaceutically acceptable salt thereof.
11. The method of claim 3 , wherein the compound has the following structure:
12. The method of claim 1 , wherein the inflammatory respiratory disease is selected from idiopathic pulmonary fibrosis, asthma, chronic obstructive pulmonary disease and chemically-induced lung fibrosis.
13. The method of claim 1 , wherein the inflammatory respiratory disease is idiopathic pulmonary fibrosis.
14. The method of claim 3 , wherein the inflammatory respiratory disease is selected from idiopathic pulmonary fibrosis, asthma, chronic obstructive pulmonary disease and chemically-induced lung fibrosis.
15. The method of claim 3 , wherein the inflammatory respiratory disease is idiopathic pulmonary fibrosis.
16. A method of treating a cancer associated with Arginase 1 or Arginase 2 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof:
wherein
R 2 is —OH or —NHR 2a ;
R 2a is —H or —C(O)CH(R 2b )NH 2 ; and
R 2b is —CH 3 or —CH(CH 3 ) 2 .
17. The method of claim 16 , wherein the compound is represented by formula (III), or a pharmaceutically acceptable salt thereof:
wherein R 3 is —CH 3 or —CH(CH 3 ) 2 .
18. A method of treating a cancer associated with Arginase 1 or Arginase 2 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (IIb), or a pharmaceutically acceptable salt thereof:
wherein
R 2 is —OH or —NHR 2a ;
R 2a is —H or —C(O)CH(R 2b )NH 2 ; and
R 2b is —CH 3 or —CH(CH 3 ) 2 .
19. The method of claim 18 , wherein the compound is represented by formula (IIIb), or a pharmaceutically acceptable salt thereof:
wherein R 3 is —CH 3 or —CH(CH 3 ) 2 .
20. The method of claim 16 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
21. The method of claim 16 , wherein the compound has the following structure:
or a pharmaceutically acceptable salt thereof.
22. The method of claim 16 , wherein the compound has the following structure:
or a pharmaceutically acceptable salt thereof.
23. The method of claim 18 , wherein the compound has the following structure:
or a pharmaceutically acceptable salt thereof.