IDO inhibitors and methods of use thereof
Novel indoleamine 2,3-dioxygenase (IDO) inhibitors, compositions comprising the same, and methods of use thereof are disclosed.
1. A compound having indoleamine 2,3 dioxygenase (IDO) inhibitory activity, said compound having the formula of:
wherein R 1 is
wherein R 3 is —NH—, —O—, or —S—; R 2 is alkenyl or —CH 2 —R 4 , wherein R 4 is hydrogen or aryl; and n is from 0 to 3; with the proviso that the compound is not brassinin.
2. The compound of claim 1 , wherein R 4 is selected from the group consisting of phenyl, naphthyl, and pyridyl.
3. The compound of claim 1 selected from the group consisting of N-[2-(Indol-3-yl)ethyl]-S-methyl-dithiocarbamate; N-[2-(benzo[b]thiophen-3-yl)ethyl]-S-methyl-dithiocarbamate; N-[3-(Indol-3-yl)propyl]-S-methyl-dithiocarbamate; S-Allyl-brassinin; S-Benzyl-brassinin; S-Hexyl-brassinin; N-[2-(indol-3-yl)ethyl]-S-benzyl-dithiocarbamate; N-[2-(indol-3-yl)ethyl]-S[(naphth-2-yl)methyl]-dithiocarbamate; N-[2-(indol-3-yl)ethyl]-S-[(pyrid-3-yl)methyl]-dithiocarbamate; and N-[2-(indol-3-yl)ethyl]-S-[(pyrid-4-yl)methyl]-dithiocarbamate.
4. The compound of claim 3 , wherein said compound is selected from the group consisting of N-[2-(benzo[b]thiophen-3-yl)ethyl]-S-methyl-dithiocarbamate;
N-[3-(Indol-3-yl)propyl]-S-methyl-dithiocarbamate; S-Allyl-brassinin; S-Benzyl-brassinin; N-[2-(indol-3-yl)ethyl]-S-benzyl-dithiocarbamate; N-[2-(indol-3-yl)ethyl]-S-[(naphth-2-yl)methyl]-dithiocarbamate; N-[2-(indol-3-yl)ethyl]-S-[(pyrid-3-yl)methyl]-dithiocarbamate; and N-[2-(indol-3-yl)ethyl]-S-[(pyrid-4-yl)methyl]-dithiocarbamate.
5. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier medium.
6. The composition of claim 5 further comprising at least one signal transduction inhibitor (STI).
7. The pharmaceutical composition of claim 6 , wherein at least one of said compounds is selected from the group consisting of N-[2-(Indol-3-yl)ethyl]-S-methyl-dithiocarbamate; N-[2-(benzo[b]thiophen-3-yl)ethyl]-S-methyl-dithiocarbamate; N-[3-(Indol-3-yl)propyl]-S-methyl-dithiocarbamate; S-Allyl-brassinin; S-Benzyl-brassinin; S-Hexyl-brassinin; N-[2-(indol 3-yl)ethyl]-S-benzyldithiocarbamate; N-[2-(indol-3-yl)ethyl]-S-[(naphth-2-yl)methyl]-dithiocarbamate; N-[2-(indol-3-yl)ethyl]-S-[(pyrid-3-yl)methyl]-dithiocarbamate; and N-[2-(indol-3-yl)ethyl]-S-[(pyrid-4-yl)methyl]-dithiocarbamate.
8. The composition of claim 5 further comprising at least one chemotherapeutic agent.
9. The composition of claim 8 , wherein at least one of said compounds is selected from the group consisting of N-[2-(Indol-3-yl)ethyl]-S-methyl-dithiocarbamate; N-[2-(benzo[b]thiophen-3-yl)ethyl]-S-methyl-dithiocarbamate; N-[3-(Indol-3-yl)propyl]S-methyl-dithiocarbamate; S-Allyl-brassinin; S-Benzyl-brassinin; S-Hexyl-brassinin; N-[2-(indol-3-yl)ethyl]-S-benzyl dithiocarbamate; N-[2-(indol-3-yl)ethyl]-S-[(naphth-2-yl)methyl]-dithiocarbamate; N-[2-(indol-3-yl)ethyl]-S[(pyrid-3-yl)methyl]-dithiocarbamate; and N-[2-(indol-3-yl)ethyl]-S-[(pyrid-4-yl)methyl]-dithiocarbamate.
10. The composition of claim 8 , wherein said at least one chemotherapeutic agent is selected from the group consisting of paclitaxel, cisplatin, docetaxol, carboplatin, vincristine, vinblastine, methotrexate, cyclophosphamide, CPT-11, 5 fluorouracil (5-FU), gemcitabine, estramustine, carmustine, adriamycin (doxorubicin), etoposide, arsenic trioxide, irinotecan, and epothilone derivatives.
11. The compound of claim 1 , wherein n is 1 to 3.
12. The compound of claim 1 , wherein said compound is N-[2-(indol-3-yl)ethyl]-S[(naphth-2-yl)methyl]-dithiocarbamate.