Abraham D J, Mehanna A S, Williams F S, Cragoe E J, Woltersdorf O W
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond 23298-0581.
J Med Chem. 1989 Nov;32(11):2460-7. doi: 10.1021/jm00131a008.
In search of a drug to treat sickle cell anemia, several analogues of the diuretic ethacrynic acid (ECA) have been synthesized and found equivalent in antigelling potency to ECA, but they have moderate or little diuretic activity. Structure-activity studies revealed that most of the highly active derivatives contain an acryloyl moiety. The latter functionality reacts covalently with protein sulfhydryl groups via a Michael addition reaction. Other derivatives, which lack the acryloyl moiety, showed notably lower antigelling activity. Since the antigelling assay is run under anaerobic conditions, activity implies a stereochemical inhibition of polymerization of deoxyhemoglobin S. The solubility ratios obtained from [HbS drug]/[HbS control] of several compounds (Table I) are near those expected for a drug with clinical potential (1.06-1.20 at tolerable doses in vivo).
为了寻找治疗镰状细胞贫血的药物，人们合成了几种利尿药依他尼酸（ECA）的类似物，发现它们在抗凝胶化效力上与ECA相当，但利尿活性中等或较弱。构效关系研究表明，大多数高活性衍生物含有丙烯酰基部分。后者通过迈克尔加成反应与蛋白质巯基发生共价反应。其他缺乏丙烯酰基部分的衍生物显示出明显较低的抗凝胶化活性。由于抗凝胶化试验是在厌氧条件下进行的，所以这种活性意味着对脱氧血红蛋白S聚合的立体化学抑制。几种化合物的[HbS药物]/[HbS对照]溶解度比（表I）接近具有临床潜力药物预期的比值（体内可耐受剂量下为1.06 - 1.20）。
