Lasserre B, Mavel S, Coudert P, Pham Huu Chanh A, Navarro-Delmasure C, Dossou-Gbete V, Couquelet J
Institut de Physiologie, Université P. Sabatier- 2F, Toulouse, France.
Prostaglandins Leukot Essent Fatty Acids. 1994 Sep;51(3):157-61. doi: 10.1016/0952-3278(94)90128-7.
A novel series of (6-aryl-4-oxo-pyrazolo 2,3-d] [1,2,5] triazin-3-yl) alkanoic acids was synthesized and evaluated in vitro as thromboxane A2 (TXA2) biosynthesis inhibitors. The experiments were carried out using arachidonic acid (32.8 microM) as a substrate and horse platelet microsomes (HPM) as sources of TXA synthetase. TXB2, a stable breakdown product of TXA2, was determined by radioimmunoassays (RIA). The substances under study, at concentrations ranging from 1.10(-6) M to 1.10(-4) M, significantly inhibited the biosynthesis of TXA2 in vitro. This activity was found to be dose-dependent, the potency of which could be related to structural features of the molecules. Compound 3b, bearing a butanoic side chain in the 3-position and a 4-chloro phenyl ring in the 6-position of the bicyclic system, was the most active derivative in in vitro enzyme inhibition (ID50 = 2.81 x 10(-5) M). Comparison of the spatial configurations of prostaglandin H2 (PGH2 and 3b displayed a good correlation between essential structural moieties of both molecules. In addition, conceptual model for the PGH2 and TX synthetase interactions was applied to compound 3b.
合成了一系列新型的(6-芳基-4-氧代-吡唑并[2,3-d][1,2,5]三嗪-3-基)链烷酸，并作为血栓素A2（TXA2）生物合成抑制剂进行了体外评估。实验以花生四烯酸（32.8 microM）为底物，以马血小板微粒体（HPM）作为TXA合成酶的来源进行。通过放射免疫分析（RIA）测定TXA2的稳定分解产物TXB2。所研究的物质在浓度范围为1.10(-6) M至1.10(-4) M时，能显著抑制体外TXA2的生物合成。发现该活性具有剂量依赖性，其效力可能与分子的结构特征有关。在双环系统的3位带有丁酸侧链且6位带有4-氯苯环的化合物3b是体外酶抑制中活性最高的衍生物（ID50 = 2.81 x 10(-5) M）。前列腺素H2（PGH2）和3b的空间构型比较显示这两个分子的基本结构部分之间具有良好的相关性。此外，将PGH2与TX合成酶相互作用的概念模型应用于化合物3b。
