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Method of modulating tigit and pd-1 signalling pathways using 1,2,4-oxadiazole compounds

A signal transduction, PD-1 technology for resistance to vector-borne diseases, organic chemistry, drug combinations, etc.

Pending Publication Date: 2020-10-27
AURIGENE DISCOVERY TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Therefore, there is still a need to develop effective treatments that exhibit dual inhibition of TIGIT and PD-1 signaling pathways, considering that there has not been much exploration of the use of TIGIT blockade in conjunction with PD-1 blockade in potentiated immune-related diseases such as cancer agent

Method used

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  • Method of modulating tigit and pd-1 signalling pathways using 1,2,4-oxadiazole compounds
  • Method of modulating tigit and pd-1 signalling pathways using 1,2,4-oxadiazole compounds
  • Method of modulating tigit and pd-1 signalling pathways using 1,2,4-oxadiazole compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0410] Example 1: ((S)-2-(3-((S)-1-amino-2-(4-hydroxyphenyl)ethyl)-1,2,4-oxadiazol-5-yl) Pyrrolidine-1-carbonyl)-L-aspartic acid (Compound 1)

[0411]

[0412] Step 1a: Synthesis of Compound 1b

[0413]

[0414] Ethyl chloroformate (4.8 g, 44.4 mmol) and NMM (4.5 g, 44.4 mmol) were added to a solution of compound 1a (10.0 g, 29.63 mmol) in THF (120 mL) and stirred at -20 °C for 20 min. After 20 minutes, 25% aqueous ammonia (30 mL) was added to the active mixed anhydride and stirred at 0-5 °C for 30 min. Reaction completion was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and partitioned between water and ethyl acetate. NaHCO 3 solution, citric acid solution and brine solution washed the organic layer. by Na 2 SO 4 The separated organic layer was dried, filtered and evaporated under reduced pressure to give 8.9 g of compound 1b. LCMS:337.4[M+H] + .

[0415] Step 1b: Synthesis of Compound 1c

[0416]

[0417] Trifluoroacetic...

Embodiment 2

[0442] Example 2: 4-((S)-2-amino-2-(5-((S)-pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)ethyl) Phenol (compound 14)

[0443]

[0444] Step 2a: Synthesis of Compound 2a

[0445]

[0446] According to the procedure described in steps 1a to 1c of Example 1 (compound 1), by using Boc-Tyr ( t Bu)-OH to synthesize compound 2a.

[0447] Step 2b: Synthesis of Compound 2b

[0448]

[0449] To a solution of Boc-Pro-OH (0.86 g, 3.41 mmol) in DMF (20 mL) was added HOBt (1.4 g, 10.6 mmol) and DIC (1.7 mL, 10.6 mmol) at 0 °C and stirred for 30 min. Compound 2a (1.8 g, 5.12 mmol) was then added at the same temperature and stirring was continued for 10 min, then at room temperature for 1 h. Reaction completion was confirmed by TLC analysis. The reaction mixture was quenched with ice water, the precipitated white solid was filtered, washed with water and dried under reduced pressure. The solid was stirred with diethyl ether (50 mL) for 15 min, filtered and dried to give 1.8 g of compou...

Embodiment 3

[0461] Example 3: Rescue of mouse splenocyte proliferation in the presence of recombinant PD-L1 / PD-L2

[0462] Recombinant mouse PD-L1 (rm-PDL-1, catalog number: 1019-B7-100; R&D Systems) was used as a source of PD-L1.

[0463] Require:

[0464]Mouse splenocytes were harvested from 6-8 week old C57 BL6 mice; RPMI 1640 (GIBCO, Cat. No. 11875); DMEM High Glucose Medium (GIBCO, Cat. No. D6429); Fetal Bovine Serum [Hyclone, Cat. No. SH30071.03 ]; penicillin (10,000 units / mL)-streptomycin (10,000 μg / mL) liquid (GIBCO, cat. no. 15140-122); MEM sodium pyruvate solution 100 mM (100x) liquid (GIBCO, cat. no. 11360); not essential Amino Acid (GIBCO, Cat. No. 11140); L-Glutamine (GIBCO, Cat. No. 25030); Anti-CD3 Antibody (eBiosciences–16-0032); Anti-CD28 Antibody (eBiosciences–16-0281); ACK Lysate (1 mL) (GIBCO, catalog number - A10492); Histopaque (density - 1.083 gm / mL) (SIGMA 10831); Trypan blue solution (SIGMA-T8154); 2 mL Norm Ject luer lock syringe (Sigma 2014-12); 40 μm nylon ce...

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Abstract

The present invention relates to method of modulating TIGIT signaling pathway and PD-1 signaling pathway. The invention also encompasses the use of the compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the treatment of diseases or disorders mediated by both TIGIT signaling pathway and PD-1 signaling pathway.

Description

[0001] related application [0002] This application claims the benefit of Indian Provisional Application No. 201841009306 filed on March 14, 2018; the specification of which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to a method for modulating a T cell immune receptor having an Ig with ITIM domain (TIGIT) and a programmed cell death-1 (PD-1) signaling pathway in a subject comprising administering the formula (I ) compound or a pharmaceutically acceptable salt thereof. Background technique [0004] Immunotherapy, which harnesses the activity of the immune system against tumors, has proven to be an effective treatment for a variety of malignancies. Indeed, through the accumulation of genetic mutations, many tumors express antigens that can potentially elicit tumor-specific immunity. However, tumors can also suppress these responses by activating negative regulatory pathways and checkpoints such as PD-1 / PD-L1 a...

Claims

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Application Information

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IPC IPC(8): A61K31/4245C07C275/06C07D271/06
CPCA61K31/4245C07D271/06C07D413/04C07D413/06C07D413/12Y02A50/30A61P35/00A61P31/00
Inventor 波塔伊尔·戈文丹·奈尔·萨斯库马穆拉利达拉·拉马钱德拉西塔拉马伊阿·塞提·苏达山·纳里马德帕里G·陈纳德
Owner AURIGENE DISCOVERY TECH
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