PD123319 is a non-peptide inhibitor of angiotensin II receptor with IC50 value of 34nM [1].
PD123319 is an antagonist of angiotensin II receptor, unlike previous drugs act as inhibitors of the formation of Ang II. PD123319 shows inhibition potency in both rat adrenal and brain binding assay with IC50 values of 34nM and 210nM, respectively. It is found to prevent Ang II from binding the bovine zona glomerulosa microsomal preparation with IC50 value of 6.9nM in the binding assay using microsome. [2,3]. PD123319 inhibited AT2 amplification product from rat pheochromocytoma cells (PC12w) binding to 0.5 nM 125I-[Sar1, Ile8]-Ang II with IC50 values of 1.7±0.2 nM [4] .In addition, it is reported that administration of PD123319 can suppress the generation of cyclic guanosine monophosphate and increase the production of prostaglandin E2[2,3].
PD123319 was transfused intra-brachial arterial in healthy young volunteers to investigated forearm vascular responses and systemic blood pressure responses. There are significant increases in mean arterial pressure were observed during intra-brachial arterial infusions of PD123319 (p = 0.003) during both placebo (80±9 to 92±17 mmHg) and telmisartan (80±11 to 90±14 mmHg) therapy, possibly in locations other than the forearm resistance vessels. Intra-brachial arterial infusion of PD123319 (10 μg/min) has significant systemic effects on rising mean arterial pressure [5].
References:
[1] Blankley C J, Hodges J C, Klutchko S R, et al.? Synthesis and structure-activity relationships of a novel series of non-peptide angiotensin II receptor binding inhibitors specific for the AT2 subtype. Journal of medicinal chemistry, 1991, 34(11): 3248-3260.
[2] Boulay G, Servant G, Luong T T, et al.? Modulation of angiotensin II binding affinity by allosteric interaction of polyvinyl sulfate with an intracellular domain of the DuP-753-sensitive angiotensin II receptor of bovine adrenal glomerulosa. Molecular pharmacology, 1992, 41(4): 809-815.
[3] Siragy H.? Angiotensin II receptor blockers: review of the binding characteristics. The American journal of cardiology, 1999, 84(10): 3-8.
[4] Kambayashi, Y., Takahashi, K., Bardhan, S. et al.?Molecular structure and function of angiotensin type2 receptor, Kidney Inr, 1994, 46, 1502- 1504.
[5] Daugherty A, Rateri DL, Howatt DA, Charnigo R, Cassis LA. PD123319 augments angiotensin II-induced abdominal aortic aneurysms through an AT2 receptor-independent mechanism. PLoS One. 2013; 8:e61849. doi: 10.1371/journal.pone.0061849.
PD123319 是血管紧张素 II 受体的非肽类抑制剂，IC50 值为 34nM [1]。
PD123319 是一种血管紧张素 II 受体拮抗剂，不同于以往的药物作为血管紧张素 II 形成抑制剂的作用。 PD123319 在大鼠肾上腺和脑结合试验中显示出抑制效力，IC50 值分别为 34nM 和 210nM。在使用微粒体的结合试验中发现它可以阻止 Ang II 与牛球状带微粒体制剂结合，IC50 值为 6.9nM。 [2,3]。 PD123319 抑制大鼠嗜铬细胞瘤细胞 (PC12w) 的 AT2 扩增产物与 0.5 nM 125I-[Sar1, Ile8]-Ang II 结合，IC50 值为 1.7±0.2 nM [4] .此外，据报道PD123319给药可抑制环磷酸鸟苷的产生，增加前列腺素E2的产生[2,3]。
PD123319 被注入健康年轻志愿者的肱动脉内，以研究前臂血管反应和全身血压反应。在安慰剂（80±9 至 92±17 mmHg）和替米沙坦（80±11 至 90±14 mmHg）治疗期间，肱动脉内输注 PD123319 (p = 0.003) 期间观察到平均动脉压显着升高，可能在前臂阻力血管以外的位置。肱动脉内输注 PD123319 (10 μg/min) 对升高平均动脉压具有显着的全身作用[5]。