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CAS No.: 1402836-58-1

IDO-IN-7 Catalog No. CSN13930

Synonyms: NLG-919 analogue;GDC-0919 analogue;Navoximod

NLG919 is a potent IDO (indoleamine-(2,3)-dioxygenase) pathway inhibitor with Ki/EC50 of 7 nM/75 nM in cell-free assays.

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靶点选择性

生物活性

实验方案

技术信息

生物活性

描述IDO1 (Indoleamine 2,3-dioxygenase-1) is a heme-containing monomeric oxidoreductase, which can catalyze the degradation of the essential amino acid tryptophan to N-formyl-kynurenine, an intermediate metabolized through a series of steps to form NAD⁺. IDO1 is considered to play an important role in the induction of tumor immune tolerance, which can regulate the immunosuppressive mechanisms responsible for tumor escape from host immune surveillance. NLG919 is potent and selective inhibitor of IDO pathway with Ki value of 7nM and EC50 value of 75nM in a cell-based assays, with 15-20 fold more selectivity to IDO than TDO. Using human pDCs^IDO1+ in allogeneic MLR reactions, NLG919 could block IDO-induced T cell suppression and restored robust T cell responses with EC50 value of 90nM, as well as with EC50 of 130nM in study using mouse pDCs^IDO1+ from tumor-draining lymph nodes. Oral administration of NLG919 dissolved in the water at 3 mg/mL markedly enhanced the anti-tumor responses of naïve and reduced the tumor growth in mice bearing large established B16F10 tumors. An addition of subcutaneous administration at 1 mg/dose twice a day via injection plus 360 µg/day via an SC osmotic pump could enhance antitumor activity^[1].
作用机制The 4-phenylimidazole structure of NLG919 could inhibit IDO1 enzyme activity in noncompetitive manner and bound the heme iron at the IDO1-active site.^[2]

动物研究

剂量

Mice: min = 50 mg/kg, max = 200 mg/kg^[2] (i.g.); 5 mg/kg^[3] (i.v.); 20 mg/kg^[3] (p.o.) Rat: 10 mg/kg - 50 mg/kg^[4] (i.v.)

给药途径

i.g., i.v., p.o.

动物药代数据

Animal	Mice^[4]	Rats^[4]	Dogs^[4]
Dose	10 mg/kg	25 mg/kg	10 mg/kg
Administration	i.v. p.o.	i.v. p.o.	i.v.
F	69% (p.o.)	60.4% (p.o.)
AUC_0→inf	6132 ng·h/ml (i.v.) 3777 ng·h/ml (p.o.)		3127 ng·h/ml
T_1/2	3.9 h (i.v.) 1.2 h (p.o.)	1.25 h (i.v.) 1.15 h (p.o.)	4.8 h
AUC_0-inf		13400 ng·h/ml (i.v.) 7975 ng·h/ml (p.o.)
CL	27.5 ml/min/kg (i.v.)	32.0 ml/min/kg (i.v.)	53.7 ml/min/kg
C_max	2257 ng/ml (p.o.)	6420 ng/ml (p.o.)

参考文献

[1] Prendergast GC, Malachowski WP, et al. Discovery of IDO1 Inhibitors: From Bench to Bedside. Cancer Res. 2017 Dec 15;77(24):6795-6811.
[2] Meng X, Du G, et al. Combinatorial antitumor effects of indoleamine 2,3-dioxygenase inhibitor NLG919 and paclitaxel in a murine B16-F10 melanoma model. Int J Immunopathol Pharmacol. 2017 Sep;30(3):215-226.
[3] Gao J, Deng F, et al. Inhibition of Indoleamine 2,3-Dioxygenase Enhances the Therapeutic Efficacy of Immunogenic Chemotherapeutics in Breast Cancer. J Breast Cancer. 2019 Apr 24;22(2):196-209.
[4] Kumar S, Waldo JP, et al. Discovery of Clinical Candidate (1R,4r)-4-((R)-2-((S)-6-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexan-1-ol (Navoximod), a Potent and Selective Inhibitor of Indoleamine 2,3-Dioxygenase 1. J Med Chem. 2019 Jul 25;62(14):6705-6733.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 3.5413 mL
- 17.7066 mL
- 35.4133 mL
- 5 mM
- 0.7083 mL
- 3.5413 mL
- 7.0827 mL
- 10 mM
- 0.3541 mL
- 1.7707 mL
- 3.5413 mL

技术信息

CAS号

1402836-58-1

储存条件

粉末: Sealed in dry,Store in freezer, under -20°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C18H22N2O

运输

蓝冰

分子量

282.38

别名

NLG-919 analogue;GDC-0919 analogue;Navoximod;GDC-0919;RG6078;(±)-NLG-919;NLG-919

溶解度

DMSO	15.0 mg/mL (53.1 mM) warming
Water	Insoluble
Ethanol	30.0 mg/mL (106.2 mM)

动物实验配方

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