Butera J, Bagli J, Doubleday W, Humber L, Treasurywala A, Loughney D, Sestanj K, Millen J, Sredy J
Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.
J Med Chem. 1989 Apr;32(4):757-65. doi: 10.1021/jm00124a006.
The design and synthesis of phenalene 26 (AY-31,358), an unsubstituted analogue of a tolrestat/ICI-105,552 computer-generated hybrid (7), are reported. Compound 7 was designed by the superimposition of the putative low-energy conformers of tolrestat (1) and ICI-105,552 (6). The more rigid aldose reductase inhibitor sorbinil (2) was used as a template to help discern a common pharmacophore in the three inhibitors. Compound 26 was synthesized as a model and was evaluated as an inhibitor of bovine lens aldose reductase. It was found to exhibit good in vitro activity as well as some in vivo activity in the nerve. It was expected that introduction of the trifluoromethyl and methoxy substituents would enhance the biological activity of model compound 26. As a result of a positive Ames test with 26, however, work has now been directed toward modifying the template in a way so as to eliminate the mutagenicity with retention of biological activity.
据报道，菲烯26（AY - 31,358）的设计与合成，它是托瑞司他/ ICI - 105,552计算机生成的杂合物（7）的未取代类似物。化合物7是通过叠加托瑞司他（1）和ICI - 105,552（6）假定的低能量构象异构体设计而成。更刚性的醛糖还原酶抑制剂索比尼尔（2）被用作模板，以帮助识别这三种抑制剂中的共同药效基团。化合物26作为模型被合成，并被评估为牛晶状体醛糖还原酶的抑制剂。发现它在体外具有良好的活性，并且在神经中具有一定的体内活性。预期引入三氟甲基和甲氧基取代基会增强模型化合物26的生物活性。然而，由于26的Ames试验呈阳性，目前的工作已转向以某种方式修饰模板，以消除致突变性并保留生物活性。
