Malamas M S, Hohman T C
Wyeth-Ayerst Research Inc., Princeton, New Jersey 08543-8000.
J Med Chem. 1994 Jun 24;37(13):2059-70. doi: 10.1021/jm00039a018.
The isoquinoline-1,3-dione framework featured in our clinical candidate (1) and its congener was used as the template in the design of several new series of aldose reductase inhibitors (ARIs). These series included N'-substituted spirosuccinimide, spiropyridazine, spiroazetidine, and acetic acid analogues. Compounds within these series were evaluated in vitro for their ability to inhibit glyceraldehyde reduction by bovine lens aldose reductase and in vivo by their ability to inhibit galactitol accumulation in the lens and sciatic nerve of galactose-fed rats. The N'-amino- and N'-alkyl-substituted spiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)- tetrones 6 exhibited high oral potency, even though they were devoid of any intrinsic activity for the aldose reductase enzyme. Similar results were observed for the closely related spiropyridazines 8. Both of these groups are also considered to be prodrugs since they exhibited good oral potency, even though they were devoid of any intrinsic activity for the aldose reductase enzyme. In contrast, the isoquinoline-1,3-dione acetic acids 9 exhibited very high intrinsic activity for the aldose reductase enzyme, although minimal or no in vivo activity. The absence of in vivo activity for some of these compounds may be due to poor tissue penetration. In support of this suggestion, the more lipophilic acetyl alkyl carbamate derivatives of these isoquinoline-1,3-dione acetic acids, exhibited enhanced oral potency. The spiroazetidines 7 exhibited good activity for the aldoe reductase enzyme in both the in vitro and in vivo assays. The findings of this study demonstrate the utility of the isoquinoline-1,3-dione framework, as a versatile template for the design of divese series of potent ARIs.
我们临床候选药物（1）及其同系物中具有的异喹啉-1,3-二酮骨架被用作设计几个新系列醛糖还原酶抑制剂（ARIs）的模板。这些系列包括N'-取代的螺琥珀酰亚胺、螺哒嗪、氮杂环丁烷和乙酸类似物。对这些系列中的化合物进行了体外评估，以测定它们抑制牛晶状体醛糖还原酶还原甘油醛的能力，并在体内评估它们抑制喂食半乳糖的大鼠晶状体和坐骨神经中半乳糖醇积累的能力。N'-氨基和N'-烷基取代的螺[异喹啉-4(1H),3'-吡咯烷]-1,2',3,5'(2H)-四酮6表现出高口服活性，尽管它们对醛糖还原酶没有任何内在活性。与它们密切相关的螺哒嗪8也观察到了类似结果。这两个组也被认为是前药，因为它们表现出良好的口服活性，尽管它们对醛糖还原酶没有任何内在活性。相比之下，异喹啉-1,3-二酮乙酸9对醛糖还原酶表现出非常高的内在活性，尽管体内活性最小或没有。这些化合物中一些缺乏体内活性可能是由于组织渗透性差。支持这一观点的是，这些异喹啉-1,3-二酮乙酸的亲脂性更强的乙酰烷基氨基甲酸酯衍生物表现出增强的口服活性。氮杂环丁烷7在体外和体内试验中对醛糖还原酶都表现出良好的活性。本研究结果证明了异喹啉-1,3-二酮骨架作为设计多种强效ARIs系列的通用模板的实用性。
