Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin
Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin
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DOI：
10.1021/acsmedchemlett.6b00491
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发表时间：
2017-03-01
影响因子：
4.2
通讯作者：
Li, Zhe
中科院分区：
文献类型：
--
作者：
Metcalf, Brian;Chuang, Chihyuan;Li, Zhe
我们报道了一种新的有效的镰状细胞血红蛋白变构效应的发现，GBT440(36)，它增加了血红蛋白对氧气的亲和力，从而在低氧条件下抑制了它的聚合。与早期的变构激活剂以2：1的化学计量比与血红蛋白共价结合不同，36以1：1的化学计量比结合。化合物36具有口服生物利用度，并以类似于150的RBC/血浆比率高度和有利地分配到红细胞中。这种对靶蛋白的分配有望使红细胞在低血浆浓度下达到治疗浓度。GBT440(36)正处于治疗镰状细胞病的第三阶段临床试验(NCT03036813)。
We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 (36), that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, 36 binds with a 1:1 stoichiometry. Compound 36 is orally bioavailable and partitions highly and favorably into the red blood cell with a RBC/plasma ratio of similar to 150. This partitioning onto the target protein is anticipated to allow therapeutic concentrations to be achieved in the red blood cell at low plasma concentrations. GBT440 (36) is in Phase 3 clinical trials for the treatment of sickle cell disease (NCT03036813).