Randad R S, Mahran M A, Mehanna A S, Abraham D J
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond 23298-0581.
J Med Chem. 1991 Feb;34(2):752-7. doi: 10.1021/jm00106a041.
Three isomeric series of 2-(aryloxy)-2-methylpropionic acids were prepared and studied for their ability to decrease the oxygen affinity of human hemoglobin A. The isomeric aryloxy groups included 4-[[(aryloyl)amino]methyl]phenoxy, 4-(arylacetamido)phenoxy, and 4-[[(arylamino)carbonyl]methyl]phenoxy. A total of 20 compounds were synthesized and tested. Structure-activity relationships are presented. Several of the new compounds were found to be strong allosteric effectors of hemoglobin. The two most active compounds are 2-[4-[[(3,5-dichloroanilino)carbonyl]-methyl]phenoxy]- 2-methylpropionic acid and the corresponding 3,5-dimethyl derivative. The latter two compounds have been compared to other known potent allosteric effectors in the same assay and show greater activity. Both compounds also exhibit a right shift in the oxygen equilibrium curve when incubated with whole blood. The new compounds may be of interest in clinical or biological areas that require or would benefit from a reversal of depleted oxygen supply (i.e., ischemia, stroke, tumor radiotherapy, blood storage, blood substitutes, etc.). They are also structurally related to several marketed antilipidemic agents.
制备了三个系列的2-(芳氧基)-2-甲基丙酸异构体，并研究了它们降低人血红蛋白A氧亲和力的能力。异构体芳氧基包括4-[[(芳酰基)氨基]甲基]苯氧基、4-(芳基乙酰胺基)苯氧基和4-[[(芳基氨基)羰基]甲基]苯氧基。总共合成并测试了20种化合物。给出了构效关系。发现几种新化合物是血红蛋白的强效别构效应剂。两种活性最高的化合物是2-[4-[[(3,5-二氯苯胺基)羰基]甲基]苯氧基]-2-甲基丙酸和相应的3,5-二甲基衍生物。在相同的测定中，将后两种化合物与其他已知的强效别构效应剂进行了比较，结果显示它们具有更高的活性。当与全血一起孵育时，这两种化合物的氧平衡曲线也都出现右移。这些新化合物可能在需要逆转氧供应不足（即缺血、中风、肿瘤放疗、血液储存、血液替代品等）或会从中受益的临床或生物学领域具有重要意义。它们在结构上还与几种已上市的抗血脂药物相关。
