Winiecka Iwona, Jaworski Paweł, Mazurek Aleksander Paweł, Marszałek Dorota, Goldnik Anna, Sokulski Daniel
Department of Drug Chemistry, Medical University of Warsaw, Banacha 1, 02 - 097, Warsaw, Poland.
J Pept Sci. 2016 Feb;22(2):106-15. doi: 10.1002/psc.2846. Epub 2016 Jan 19.
In search for new drugs lowering arterial blood pressure, which could be applied in anti-hypertensive therapy, research concerning agents blocking of renin-angiotensin-aldosteron system has been conducted. Despite many years of research conducted at many research centers around the world, aliskiren is the only one renin inhibitor, which is used up to now. Four novel potential renin inhibitors, having structure based on the peptide fragment 8-13 of human angiotensinogen, a natural substrate for renin, were designed and synthesized. All these inhibitors contain unnatural moieties that are derivatives of N-methylleucyl-β-hydroxy-γ-amino acids at the P2-P1' position: 4-[N-(N-methylleucyl)-amino]-3-hydroxy-7-(3-nitroguanidino)-heptanoic acid (AHGHA), 4-[N-(N-methylleucyl)-amino]-3-hydroxy-5-phenyl-pentanoic acid (AHPPA) or 4-[N-(N-methylleucyl)-amino]-8-benzyloxycarbonylamino-3-hydroxyoctanoic acid (AAHOA). The previously listed synthetic β-hydroxy-γ-amino acids constitute pseudodipeptidic units that correspond to the P1-P1' position of the inhibitor molecule. An unnatural amino acid, 4-methoxyphenylalanin (Phe(4-OMe)), was introduced at the P3 position of the obtained compounds. Three of these compounds contain isoamylamide of 6-aminohexanoic acid (ε-Ahx-Iaa) at the P2'-P3' position. The proposed modifications of the selected human angiotensinogen fragment are intended to increase bioactivity, bioavailability, and stability of the inhibitor molecule in body fluids and tissues. The inhibitor Boc-Phe(4-OMe)-MeLeu-AHGHA-OEt was obtained in the form of an ethyl ester. The hydrophobicity coefficient, expressed as log P varied between 3.95 and 8.17. In vitro renin inhibitory activity of all obtained compounds was contained within the range 10(-6)-10(-9) M. The compound Boc-Phe(4-OMe)-MeLeu-AHPPA-Ahx-Iaa proved to be the most active (IC50 = 1.05 × 10(-9) M). The compounds Boc-Phe(4-OMe)-MeLeu-AHGHA-Ahx-Iaa and Boc-Phe(4-OMe)-MeLeu-AHPPA-Ahx-Iaa are resistant to chymotrypsin.
为寻找可用于抗高血压治疗的新型降动脉血压药物，开展了有关阻断肾素 - 血管紧张素 - 醛固酮系统药物的研究。尽管世界各地的许多研究中心进行了多年研究，但阿利吉仑是目前唯一使用的肾素抑制剂。设计并合成了四种基于人血管紧张素原（肾素的天然底物）的肽片段8 - 13结构的新型潜在肾素抑制剂。所有这些抑制剂在P2 - P1'位置都含有非天然部分，即N - 甲基亮氨酰 - β - 羟基 - γ - 氨基酸的衍生物：4 - [N - (N - 甲基亮氨酰) - 氨基] - 3 - 羟基 - 7 - (3 - 硝基胍基) - 庚酸（AHGHA）、4 - [N - (N - 甲基亮氨酰) - 氨基] - 3 - 羟基 - 5 - 苯基 - 戊酸（AHPPA）或4 - [N - (N - 甲基亮氨酰) - 氨基] - 8 - 苄氧羰基氨基 - 3 - 羟基辛酸（AAHOA）。前面列出的合成β - 羟基 - γ - 氨基酸构成了与抑制剂分子P1 - P1'位置相对应的拟二肽单元。在所得化合物的P3位置引入了非天然氨基酸4 - 甲氧基苯丙氨酸（Phe(4 - OMe)）。这些化合物中的三种在P2' - P3'位置含有6 - 氨基己酸异戊酰胺（ε - Ahx - Iaa）。对所选人血管紧张素原片段的拟修饰旨在提高抑制剂分子在体液和组织中的生物活性、生物利用度和稳定性。抑制剂Boc - Phe(4 - OMe) - MeLeu - AHGHA - OEt以乙酯形式获得。以log P表示的疏水系数在3.95至8.17之间变化。所有所得化合物的体外肾素抑制活性在10(-6) - 10(-9) M范围内。化合物Boc - Phe(4 - OMe) - MeLeu - AHPPA - Ahx - Iaa被证明是活性最高的（IC50 = 1.05×10(-9) M）。化合物Boc - Phe(4 - OMe) - MeLeu - AHGHA - Ahx - Iaa和Boc - Phe(4 - OMe) - MeLeu - AHPPA - Ahx - Iaa对胰凝乳蛋白酶具有抗性。
