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. PF-06840003 is a selective IDO1 inhibitor with IC50 values of 0.41μM, 0.59μM and 1.5μM for hIDO-1, dIDO-1 and mIDO-1 (measured by enzymic acitivity), respectively. PF-06840003 is a racemic mixture, of which only the R-isomer is active, in development due to rapid epimerization of the chiral carbon that is adjacent to a carbonyl group. Incubation with PF-06840003 for 24h also showed significant inhibition on kynurenine production in HeLa, THP and human whole blood cells induced by INFγ or LPS^[1], and reversed intratumoral KYN levels by >80% in vivo^[2]. Oral administration of the PF-06840003 achieved total brain to plasma Kp ratio 0.51, indicating the brain penetrance of this compound^[1]. Combination of PF-06840003 with immunotherapies including antibodies against PD-1 showed inhibition of tumor growth in multiple mouse syngeneic models^[2].
• 作用机制PF-06840003 forms H-bond interaction with the propionate of the heme, not the heme iron atom, which is differently from most of the IDO-1 inhibitors described so far.^[1]

• 动物研究
  剂量	Mice[2] (p.o.): 20 mg/kg - 1200mg/kg
  给药途径	p.o.
  动物药代数据	Animal Mice[1] Rats[1] Dogs[1] Dose 3 mg/kg 3 mg/kg 3 mg/kg Administration p.o. p.o. p.o. F 0.593 0.94 0.186 AUCinf 2170 ng·h/ml 6940 ng·h/ml 237 ng·h/ml T1/2 2.48 h 2.42 h 0.84 h Tmax 0.58 h 1.3 h 0.25 h Cmax 538 ng/ml 985 ng/ml 219 ng/ml