Seiler S M, Brassard C L, Federici M E, Romine J, Meanwell N A
Department of Cardiovascular, Bristol-Myers Squibb Pharmaceutical Research Institute Wallingford, CT, USA.
Prostaglandins. 1997 Jan;53(1):21-35. doi: 10.1016/s0090-6980(96)00138-4.
[3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid (BMY 45778) inhibits human (IC50 = 35 nM), rabbit (136 nM) and rat (1.3 microM) platelet aggregation. This compound activates adenylyl cyclase (ED50 = 6-10 nM) and stimulates GTPase in human platelet membrane preparations. The potency (EC50) of BMY 45778 stimulating adenylyl cyclase is comparable to iloprost. However, maximal stimulation of GTPase by BMY 45778 is approximately half the iloprost-stimulated activity, and BMY 45778 limits the GTPase stimulation by iloprost suggesting that BMY 45778 is a partial agonist at the IP receptor. BMY 45778 completely prevents [3H]]Iloprost binding to platelet membranes (IC50 = 7 nM). In whole platelets, BMY 45778 causes elevation of platelet cAMP levels (cAMP content doubles at 13 nM) and activation of the cAMP-dependent protein kinase (cAMP-protein kinase ratio is twice basal at 2 nM). BMY 45778 treatment of whole platelets also desensitizes the adenylyl cyclase activation by iloprost. These results indicate that BMY 45778, which is structurally different from prostacyclin and most prostacyclin agonists, acts by stimulating prostacyclin (IP) receptors.
[3-[4-(4,5-二苯基-2-恶唑基)-5-恶唑基]苯氧基]乙酸(BMY 45778)可抑制人(IC50 = 35 nM)、兔(136 nM)和大鼠(1.3 μM)的血小板聚集。该化合物可激活腺苷酸环化酶(ED50 = 6 - 10 nM)并刺激人血小板膜制剂中的GTP酶。BMY 45778刺激腺苷酸环化酶的效力(EC50)与伊洛前列素相当。然而,BMY 45778对GTP酶的最大刺激作用约为伊洛前列素刺激活性的一半,并且BMY 45778会限制伊洛前列素对GTP酶的刺激,这表明BMY 45778是IP受体的部分激动剂。BMY 45778可完全阻止[3H]伊洛前列素与血小板膜结合(IC50 = 7 nM)。在全血小 板中,BMY 45778可使血小板cAMP水平升高(在13 nM时cAMP含量翻倍)并激活cAMP依赖性蛋白激酶(在2 nM时cAMP - 蛋白激酶比值是基础值的两倍)。用BMY 45778处理全血小 板还会使伊洛前列素对腺苷酸环化酶的激活作用脱敏。这些结果表明,BMY 45778在结构上与前列环素和大多数前列环素激动剂不同,它通过刺激前列环素(IP)受体发挥作用。