PgH2 analogs as potential antiplatelet derivatives.
PgH2 analogs as potential antiplatelet derivatives.
复制标题
PgH2 类似物作为潜在的抗血小板衍生物。
DOI：
10.1021/jm00094a017
复制
发表时间：
1992
影响因子：
7.3
通讯作者：
Venton,DL
中科院分区：
文献类型：
--
作者：
Komiotis,D;Lim,CT;Dieter,JP;LeBreton,GC;Venton,DL
以前的观察牵连PgH 2作为血小板的直接激活剂表明，衍生物的U46619，一个良好的特点TxA 2受体激动剂与PgH 2的结构同源性，可能具有抗血小板活性。本工作描述了[1 S-（1a，20，3a，4a）]-3-[（四氢吡喃氧基）甲基]-2-[2-[（三苯基甲基）氧基]乙基]-5-氧杂双环[2.2. 1]庚烷（14）是合成各种环氧亚甲基衍生物的潜在有用的中间体。将后者转化为[1 S-（1a，20（Z），3a，4a）]-7-[3-[[2-[（苯基氨基）羰基]-肼基]甲基]-5-氧杂双环[2.2. 1]庚-2-基]-5-庚烯酸（23），PgH 2的环氧甲烷衍生物，其含有酰肼下侧链，如先前在TxA 2拮抗剂中使用的，SQ 29，548。中间体14也转化为[1 S-（la，20（Z），3a，4a）]-7-[3-[（己基氨基）甲基]-5-氧杂双环[2.2. 1]庚-2-基]-5-庚烯酸（25），其含有如早期拮抗剂中所用的简单氮杂侧链。衍生物23和25似乎是人血小板TxA 2受体的特异性拮抗剂，这通过它们抑制U46619（1.5 μ）诱导的人富血小板血浆聚集（IC 50分别为22和7 μ）来证明，而在高得多的浓度下对ADP（2 μ）诱导的聚集几乎没有影响。此外，这些衍生物之一双环胺25显示出与[3 H] U46619竞争结合洗涤的人血小板，IC 50值为25 µ，支持这些衍生物作用于血栓烷受体的观点。然而，这些衍生物的效力低于以前报道的TxA 2拮抗剂，这表明来自对人血小板血栓烷受体有活性的分子的功能性的简单线性组合将具有有限的预测价值。后者的工作已经产生了许多不同的结构，据报道是特定的TxA 2受体。对TxA 2的强调逻辑上源于血小板中TxA 2的产生是花生四烯酸激活血小板的先决条件的原始概念。然而，有证据表明PgH 2（2）本身可直接刺激血小板功能变化，10 PgH 2与血小板受体的相互作用似乎与钙动员有关，因此推测血小板功能变化。11 12此外，至少一种最佳表征的TxA 2受体激动剂U46619
Previous observations implicating PgH2 as a direct activator of platelets suggested that derivatives of U46619, a well-characterized TxA2 receptor agonist having structural homology with PgH2, might possess antiplatelet activity. The present work describes the synthesis of [lS-(la, 20, 3a, 4a)]-3-[(tetrahydropyranyloxy) methyl]-2-[2-[(tri-phenylmethyl) oxy] ethyl]-5-oxabicyclo [2.2. 1] heptane (14) a potentially useful intermediate for the synthesis of various epoxymethano derivatives. Thelatter was converted to [lS-(la, 20 (Z), 3a, 4a)]-7-[3-[[2-[(phenylamino) carbonyl]-hydrazino] methyl]-5-oxabicyclo [2.2. 1] hept-2-yl]-5-heptenoic acid (23), an epoxymethano derivative of PgH2 containing a hydrazide lower side chain as previously used in the TxA2 antagonist, SQ29, 548. The intermediate 14 was also converted to [lS-(la, 20 (Z), 3a, 4a)]-7-[3-[(hexylamino) methyl]-5-oxabicyclo [2.2. 1] hept-2-yl]-5-heptenoic acid (25) which contained a simple aza side chain as used in earlierantagonists. Derivatives 23 and 25 appeared to be specific antagonists of the human platelet TxA2 receptor as evidenced by their inhibition of U46619 (1.5 µ) induced aggregation of human plateletrich plasma (IC50= 22 and 7 µ, respectively), while having little effect on ADP (2 µ) induced aggregation at much higher concentrations. In addition, one of these derivatives, the bicycloamine 25, was shown to compete for [3H] U46619 binding to washed human platelets with an IC50 value of 25 µ, supporting the notion that these derivatives were acting at the thromboxane receptor. However, the potency of these derivatives was less than for previously reported TxA2 antagonists, suggesting that simple linear combinations of functionality from molecules active at the human platelet thromboxane receptor will be of limited predictive value.Considerable effort has been expended in an attempt to find specific TxA2 (1) synthase inhibitors and TxA2 receptor antagonists as potential antithrombotic agents. The latter work has resulted in a number of diverse structures which are reported to be specific TxA2 antag-onists. 1" 9 The emphasis on TxA2 logically stems from the original notion that TxA2 production in the platelet was prerequisite to platelet activation by arachidonic acid. Yet evidence has indicated that PgH2 (2) itself is directly ca-pable of stimulating platelet functional change, 10 and interaction of PgH2 with the platelet receptorappears to be coupled to calcium mobilization and thus presumably platelet functional change. 11 12In addition, at least one of the best characterized TxA2 receptor agonists, U46619