Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
J Med Chem. 2011 Jun 9;54(11):3779-92. doi: 10.1021/jm200036n. Epub 2011 May 9.
Macrocyclic analogues of angiotensin IV (Ang IV, Val(1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6)) targeting the insulin-regulated aminopeptidase (IRAP) have been designed, synthesized, and evaluated biologically. Replacement of His(4)-Pro(5)-Phe(6) by a 2-(aminomethyl)phenylacetic acid (AMPAA) moiety and of Val(1) and Ile(3) by amino acids bearing olefinic side chains followed by macrocyclization provided potent IRAP inhibitors. The impact of the ring size and the type (saturated versus unsaturated), configuration, and position of the carbon-carbon bridge was assessed. The ring size generally affects the potency more than the carbon-carbon bond characteristics. Replacing Tyr(2) by β(3)hTyr or Phe is accepted, while N-methylation of Tyr(2) is deleterious for activity. Removal of the carboxyl group in the C-terminal slightly reduced the potency. Inhibitors 7 (K(i) = 4.1 nM) and 19 (K(i) = 1.8 nM), both encompassing 14-membered ring systems connected to AMPAA, are 10-fold more potent than Ang IV and are also more selective over aminopeptidase N (AP-N). Both compounds displayed high stability against proteolysis by metallopeptidases.
已设计、合成并评估了针对胰岛素调节氨肽酶（IRAP）的血管紧张素 IV（Ang IV，Val（1）-Tyr（2）-Ile（3）-His（4）-Pro（5）-Phe（6））的大环类似物。用 2-（氨甲基）苯乙酸（AMPAA）取代 His（4）-Pro（5）-Phe（6），用带有烯烃侧链的氨基酸取代 Val（1）和 Ile（3），然后进行大环化，得到了有效的 IRAP 抑制剂。评估了环大小以及碳-碳键的类型（饱和与不饱和）、构型和位置的影响。环大小通常比碳-碳键特征对效力的影响更大。接受用 β（3）hTyr 或 Phe 取代 Tyr（2），而 Tyr（2）的 N-甲基化则对活性有害。去除 C 末端的羧基基团会略微降低效力。包含与 AMPAA 相连的 14 元环系统的抑制剂 7（K(i) = 4.1 nM）和 19（K(i) = 1.8 nM）比 Ang IV 强 10 倍，对氨肽酶 N（AP-N）的选择性也更高。这两种化合物对金属肽酶的蛋白水解都具有很高的稳定性。
