Manley P W, Tuffin D P, Allanson N M, Buckle P E, Lad N, Lai S M, Lunt D O, Porter R A, Wade P J
Department of Biology, Searle Research and Development, Division of G. D. Searle & Co. Ltd., Buckinghamshire, U.K.
J Med Chem. 1987 Oct;30(10):1812-8. doi: 10.1021/jm00393a022.
A series of substituted omega-[2-(1H-imidazol-1-yl)ethoxy]alkanoic acid derivatives were synthesized and evaluated for their ability to inhibit thromboxane synthase both in vitro and in vivo. Compound 13 was identified as a potent and selective competitive inhibitor of human platelet thromboxane synthase having a Ki value of 9.6 X 10(-8) M. In collagen-treated human whole blood, 13 potentiated levels of 6-keto PGF1 alpha. Enantiospecific syntheses afforded the R and S enantiomers of 13, of which the S enantiomer 13b was the more potent. Compounds 13 and 13b were potent in vivo inhibitors of thromboxane synthase with good oral activity and duration of action.
合成了一系列取代的ω-[2-(1H-咪唑-1-基)乙氧基]链烷酸衍生物，并对其在体外和体内抑制血栓素合酶的能力进行了评估。化合物13被鉴定为人类血小板血栓素合酶的一种强效且选择性的竞争性抑制剂，其Ki值为9.6×10(-8) M。在胶原蛋白处理的人全血中，13增强了6-酮-PGF1α的水平。对映体特异性合成得到了13的R和S对映体，其中S对映体13b活性更强。化合物13和13b是血栓素合酶的强效体内抑制剂，具有良好的口服活性和作用持续时间。
