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.) AUC0→inf 6132 ng·h/ml (i.v.) 3777 ng·h/ml (p.o.) 3127 ng·h/ml T1/2 3.9 h (i.v.) 1.2 h (p.o.) 1.25 h (i.v.) 1.15 h (p.o.) 4.8 h AUC0-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 Cmax 2257 ng/ml (p.o.) 6420 ng/ml (p.o.)