Paruszewski R, Jaworski P, Tautt J, Dudkiewicz J
Department of Pharmaceutical Chemistry, Medical University, Warszawa, Poland.
Boll Chim Farm. 1995 Nov;134(10):551-6.
Four new compounds: Nic-Phe/4-OMe/-MePhe-Sta-epsilonAhx-OMe/23/,Nic-Phe/4-OMe/-MePhe- Sta-epsilonAhx-Iaa/24/,iNic-Phe/4-OMe/-MeLeu-Sta-ep silonAhx-OMe/29/ and iNic-Phe/4-OMe/-MeLeu-Sta-epsilonAhx-Iaa/30/ have been synthesized in search after renin inhibitors of improved biological properties. Their stability against chymotrypsin activity, solubility in water at pH 7.4, 6.9 and 2.0, partition coefficient and activity in vitro were determined. All synthesized inhibitors are resistant to enzymatic degradation, all are very good soluble in water at pH 2.0, poorly soluble at pH 6.9 and insoluble at pH 7.4. Partition coefficients go up together with increase of pH worth of buffer. IC50 of obtained inhibitors 23,24,29 and 30 is 3 x 10(-4),7.5 x 10(-4),4 x 10(5) and 4 x 10(-3)M/1 respectively.
为了寻找具有更好生物学特性的肾素抑制剂，已合成了四种新化合物：Nic-Phe/4-OMe/-MePhe-Sta-εAhx-OMe/23/、Nic-Phe/4-OMe/-MePhe-Sta-εAhx-Iaa/24/、iNic-Phe/4-OMe/-MeLeu-Sta-εAhx-OMe/29/和iNic-Phe/4-OMe/-MeLeu-Sta-εAhx-Iaa/30/。测定了它们对胰凝乳蛋白酶活性的稳定性、在pH 7.4、6.9和2.0时在水中的溶解度、分配系数和体外活性。所有合成的抑制剂均对酶解具有抗性，在pH 2.0时均极易溶于水，在pH 6.9时溶解性较差，在pH 7.4时不溶。分配系数随缓冲液pH值的升高而增大。所得到的抑制剂23、24、29和30的IC50分别为3×10⁻⁴、7.5×10⁻⁴、4×10⁵和4×10⁻³M/1。
