1,2,4-Oxadiazole Derivatives as Immunomodulators
The present invention relates to 1,2,4-oxadiazole and 1,2,4-thiadiazole compounds as therapeutic agents capable of inhibiting the programmed cell death 1 (PD1) signaling pathway. The invention also refers to derivatives of the therapeutic agents. The invention also encompasses the use of the said therapeutic agents and derivatives for treatment of disorders via immunopotentiation comprising inhibition of immunosuppressive signal induced due to PD-1, PD-L1, or PD-L2 and therapies using them.
1 . A compound of formula (I)
wherein,
Q is S or O;
R 1 is a side chain of amino acid Ser or Thr, optionally substituted with alkyl or acyl;
R 2 is hydrogen or —CO-Aaa;
Aaa is an amino acid residue Thr or Ser; wherein a C-terminus thereof is a free terminus, is amidated or is esterified;
R 3 is a side chain of amino acid Asn, Asp, Gln, or Glu;
----- is an optional bond;
R 4 and R 5 independently are hydrogen or absent;
R 6 is hydrogen, alkyl or acyl;
or a pharmaceutically acceptable salt or a stereoisomer thereof.
2 . The compound according to claim 1 , wherein the compound of formula (I) is a compound of formula (IA):
or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,
R 1 is a side chain of amino acid Ser or Thr, optionally substituted with alkyl or acyl;
R 3 is a side chain of amino acid Asn, Asp, Gln, or Glu; and
Aaa is an amino acid residue Thr or Ser; wherein a C-terminus thereof is a free terminus, is amidated or is esterified.
3 . The compound according to claim 1 , wherein the compound of formula (I) is a compound of formula (IB):
or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,
R 1 is a side chain of amino acid Ser or Thr, optionally substituted with alkyl or acyl; and
R 3 is a side chain of amino acid Asn, Asp, Gln, or Glu.
4 . The compound according to claim 1 , wherein
R 1 is a side chain of amino acid residue Ser or Thr;
R 2 is —CO-Aaa;
Aaa is an amino acid residue Thr or Ser; wherein the C-terminus is free; and
R 3 is a side chain of amino acid residue Asn or Glu.
5 . The compound according to claim 1 , wherein Q is O.
6 . The compound according to claim 1 , wherein R 6 is —C(O)CH 3 , —C(O)CH 2 CH 3 , —C(O)(CH 2 ) 2 CH 3 , —C(O)(CH 2 ) 3 CH 3 , —C(O)(CH 2 ) 4 CH 3 or —C(O)(CH 2 ) 5 CH 3 .
7 . The compound according to claim 1 , wherein the compound of formula (I) has a structure selected from the group consisting of
Compound
No.
Structure
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
or a pharmaceutically acceptable salt or a stereoisomer thereof.
8 . A pharmaceutical composition comprising at least one compound according to claim 1 or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
9 . The pharmaceutical composition according to claim 8 further comprising at least one of an anticancer agent, chemotherapy agent, or antiproliferative compound.
10 . A method of modulating an immune response mediated by PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
11 . A method of inhibiting growth of tumour cells and/or metastasis in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
12 . The method of claim 11 , wherein the tumour cells are from a cancer selected from the group consisting of breast cancer, colon cancer, lung cancer, melanoma, prostate cancer, and renal cancer.
13 . The method of claim 11 , wherein the tumour cells are from a cancer selected from the group consisting of bone cancer, cancer of the head or neck, pancreatic cancer, skin cancer, cutaneous or intraocular malignant endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hogkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumours of childhood, lymphocytic lymphoma cancer of the bladder, cancer of the kidney or reter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumour angiogenesis, spinal axis tumour, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers.
14 . A method of treating an infectious disease in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
15 . A method of treating bacterial, viral and fungal infections in a subject comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
16 . A compound having a structural formula selected from the group consisting of
Compound
No.
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
or a pharmaceutically acceptable salt or a stereoisomer thereof.
17 . A pharmaceutical composition comprising at least one of the compounds according to claim 16 and a pharmaceutically acceptable carrier or excipient.
18 . A method for treating a cancer or infectious disease, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 17 .
19 . The method according to claim 18 , wherein the cancer is breast cancer, colon cancer, lung cancer, melanoma, prostate cancer, or renal cancer.
20 . The method according to claim 18 , wherein the infectious disease is a bacterial infectious disease, a viral infectious disease or a fungal infectious disease.