Department of Food Science and Engineering, School of Food and Drug, Luoyang Normal University, Luoyang 471934, People's Republic of China.
Cancer Institute, Fudan University Cancer Hospital and Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, People's Republic of China.
Drug Des Devel Ther. 2020 Mar 5;14:977-992. doi: 10.2147/DDDT.S225705. eCollection 2020.
This study aimed to synthesize twin drugs from cinnamic acid compounds, caffeic acid (CFA) and ferulic acid (FLA), which can antagonize endothelin-1 (ET-1) with telmisartan through ester bonds. Moreover, the antihypertensive effect of telmisartan and its influence on blood pressure variability (BPV) were enhanced, and the bioavailability of caffeic acid and ferulic acid was improved.
Six twin drugs, which were the target compounds, were synthesized. Hypertensive rats (SHR) and conscious sinoaortic-denervated (SAD) rats were spontaneously used as models for pharmacodynamic research to study the antihypertensive efficacy of these twin drugs. Wistar rats were employed as pharmacokinetic research models to investigate the pharmacokinetics of the target compounds via intragastric administration. Cellular pharmacodynamic research was also conducted on the antagonistic action on Ang II-AT1, ETA and ETB receptor.
Compound was determined as the best antihypertensive twin drug and thus was further studied for its effect on BPV. Compared with that of telmisartan, the antihypertensive effect of compound was improved (<0.05), and the BPV was reduced (<0.05). The bioavailability of caffeic acid and ferulic acid after hydrolysis from twin drugs could be increased to varying degrees, and the differences of the main pharmacokinetic parameters among the different forms of caffeic acid and ferulic acid were statistically significant (<0.05 or <0.01). Compound had the best antagonistic effect on the Ang II-AT1 receptor. However, the IC of Lps-2 was still two orders of magnitude higher than that of the positive drug telmisartan. Hence, the twin drugs worked by metabolizing and regenerating telmisartan and caffeic acid or ferulic acid in the body.
The synthesized twin drugs improved telmisartan's antihypertensive effects, significantly decreased BPV in SAD rats and increased the bioavailability of caffeic acid and ferulic acid. This study serves as a basis for the development of new angiotensin receptor blocker (ARB) in the future and a reference for the development of new drugs to antagonize ET-1.
本研究旨在合成肉桂酸化合物咖啡酸（CFA）和阿魏酸（FLA）与替米沙坦通过酯键形成的孪药，以拮抗内皮素-1（ET-1）。此外，增强了替米沙坦的降压作用及其对血压变异性（BPV）的影响，提高了咖啡酸和阿魏酸的生物利用度。
合成了 6 种目标化合物作为孪药。使用自发性高血压大鼠（SHR）和去窦弓神经（SAD）大鼠作为药效学研究模型，研究这些孪药的降压作用。采用 Wistar 大鼠作为药代动力学研究模型，通过灌胃给药研究目标化合物的药代动力学。还进行了细胞药效学研究，以研究其对 Ang II-AT1、ETA 和 ETB 受体的拮抗作用。
确定化合物 为最佳降压孪药，并进一步研究其对 BPV 的影响。与替米沙坦相比，化合物 的降压作用得到改善（<0.05），BPV 降低（<0.05）。从孪药水解后，咖啡酸和阿魏酸的生物利用度可不同程度提高，且不同形式的咖啡酸和阿魏酸的主要药代动力学参数差异有统计学意义（<0.05 或 <0.01）。化合物 对 Ang II-AT1 受体的拮抗作用最好。然而，Lps-2 的 IC 仍比阳性药物替米沙坦高两个数量级。因此，孪药通过在体内代谢和再生替米沙坦和咖啡酸或阿魏酸起作用。
合成的孪药提高了替米沙坦的降压作用，显著降低了 SAD 大鼠的 BPV，提高了咖啡酸和阿魏酸的生物利用度。本研究为未来开发新型血管紧张素受体阻滞剂（ARB）提供了依据，为开发拮抗 ET-1 的新药提供了参考。
