Izuhara Yuko, Sada Toshio, Yanagisawa Hiroaki, Koike Hiroyuki, Ohtomo Shuichi, Dan Takashi, Ito Sadayoshi, Nangaku Masaomi, van Ypersele de Strihou Charles, Miyata Toshio
Center for Translational and Advanced Research, Tohoku University Graduate School of Medicine, Sendai, Japan.
Arterioscler Thromb Vasc Biol. 2008 Oct;28(10):1767-73. doi: 10.1161/ATVBAHA.108.172841. Epub 2008 Jul 24.
Antihypertensive angiotensin II receptor blockers (ARBs) protect the kidney, at least in part, independently of blood pressure lowering. Still, the extent to which blood pressure lowering is related to renoprotection remains unclear.
139 newly synthesized ARB-derivatives were assayed for inhibition of advanced glycation (AGEs). The 9 most powerful compounds were then tested for transition metal chelation, angiotensin II type 1 receptor (AT1R) affinity, and pharmacokinetic parameters. R-147176 was eventually selected as it strongly inhibits advanced glycation but is 6700 times less effective than olmesartan in AT1R binding. It is orally bioavailable and toxicologically safe. Despite a minimal blood pressure lowering effect, it provides significant renoprotection in 3 experimental rat models with renal injury, ie, obese, hypertensive, type 2 diabetic rats (SHR/NDmcr-cp), normotensive type 2 diabetic rats (Zucker diabetic fatty), and remnant kidney rats.
R-147176 retains renal protective properties despite a minimal blood pressure-lowering effect. Clearly, the renal benefits of ARBs do not necessarily depend on blood pressure lowering and AT1R affinity, but rather on the inhibition of AGEs and oxidative stress inherent to their chemical structure. R-147176 opens new avenues in the treatment of cardiovascular and kidney diseases.
抗高血压血管紧张素 II 受体阻滞剂（ARB）至少部分地独立于降压作用来保护肾脏。然而，降压与肾脏保护之间的关联程度仍不清楚。
对 139 种新合成的 ARB 衍生物进行了晚期糖基化终末产物（AGEs）抑制作用的检测。然后对 9 种活性最强的化合物进行了过渡金属螯合、血管紧张素 II 1 型受体（AT1R）亲和力及药代动力学参数的测试。最终选择了 R - 147176，因为它能强烈抑制晚期糖基化，但在 AT1R 结合方面的效力比奥美沙坦低 6700 倍。它口服生物利用度良好且毒理学上安全。尽管其降压作用极小，但在 3 种肾损伤实验大鼠模型，即肥胖、高血压、2 型糖尿病大鼠（SHR/NDmcr - cp）、正常血压 2 型糖尿病大鼠（Zucker 糖尿病脂肪大鼠）和残肾大鼠中，它能提供显著的肾脏保护作用。
尽管 R - 147176 的降压作用极小，但仍保留肾脏保护特性。显然，ARB 的肾脏益处不一定取决于降压作用和 AT1R 亲和力，而是取决于对 AGEs 的抑制作用及其化学结构所固有的氧化应激抑制作用。R - 147176 为心血管和肾脏疾病的治疗开辟了新途径。
