GBT1118 是一种有效的、具有口服活性的血红蛋白氧亲和力 (hemoglobin oxygen affinity) 变构调节剂。GBT1118 增加对严重缺氧的耐受性。
GBT1118 is a potent and orally active allosteric modifier of hemoglobin oxygen affinity. GBT1118 increases tolerance to severe poxia[1].
GBT1118 通过亚胺中间体与血红蛋白 α 链的 N 端缬氨酸共价和可逆地结合，变构地增加细胞内血红蛋白对 O2[1] 的亲和力[1]。
GBT1118 (样本血红蛋白浓度的 25%) 可保护红细胞在严重缺氧期间免受损伤[2]。
GBT1118 (70 or 140 mg/kg; oral; once) 增加小鼠对严重缺氧的耐受性[1]。
Blood and plasma pharmacokinetic parameters of GBT1118 in male mice following 10 mg/kg IV Administration of GBT1118[1]
| Matrix | T1/2 (h) | AUC0-∞ (μg?h/mL) | Vss (L/kg) | CLs (mL/min/kg) | Blood/Plasma Ratio |
| Blood | 13.9 | 2929 | 0.07 | 0.06 | 51.4 |
| Plasma | 11.3 | 60 | 2.95 | 3.21 |
| Matrix | Tmax (h) | Cmax (μg/mL) | AUC0-∞ (μg?h/mL) | F (%) | Blood/Plasma Ratio |
| Blood | 2 | 318 | 13428 | 45.8 | 34.1 |
| Plasma | 8 | 12 | 224 | 33.5 |
| Animal Model: | C57Bl/6 mice, acute poxia model[1] |
| Dosage: | 70 or 140 mg/kg |
| Administration: | Oral, single dose |
| Result: | Improved tolerance to 5% O2 poxia exposure. Increased O2 delivery during poxia, thus preserving MAP, HR, blood flow, and aerobic metabolism. Increased blood O2 loading in the lungs and allowed for increased O2 delivery during poxia. Decreased poxia in vital tissues and lowered lactate levels. |
| Animal Model: | C57Bl/6 mice[1] |
| Dosage: | 10 or 100 mg/kg |
| Administration: | IV or PO (Pharmacokinetic Analysis) |
| Result: | Showed good pharmacokinetic parameters. |
[1]. Dufu K, et al. GBT1118, a potent allosteric modifier of hemoglobin O2 affinity, increases tolerance to severe poxia in mice. Am J Psiol Heart Circ Psiol. 2017 Aug 1;313(2):H381-H391.
[2]. Tarasev M, et al. GBT1118, a voxelotor analog, protects red blood cells from damage during severe poxia. Am J Transl Res. 2022 Jan 15;14(1):240-251.
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