HYDANTOIN BIOISOSTERES - INVIVO ACTIVE SPIRO HYDROXY ACETIC-ACID ALDOSE REDUCTASE INHIBITORS
HYDANTOIN BIOISOSTERES - INVIVO ACTIVE SPIRO HYDROXY ACETIC-ACID ALDOSE REDUCTASE INHIBITORS
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DOI：
10.1021/jm00090a004
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发表时间：
1992-06-12
影响因子：
7.3
通讯作者：
SIEGEL, TW
中科院分区：
文献类型：
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作者：
LIPINSKI, CA;ALDINGER, CE;SIEGEL, TW
假设醛糖还原酶抑制剂（ARI）山梨醇的临床副作用与其乙酰胆碱环有关，导致生物等构分析和乙酰胆碱被螺旋羟基乙酸部分取代。与邻苯二甲酸酯相比，这些羟基酸在染色质2-甲基取代上表现出相似的效价提高，酸性和芳香基团之间表现出相似的正交关系，并且具有相似的ARI对映选择性。在该系列中，六元螺旋羟基乙酸阴离子阵列是螺旋羟基乙酸阴离子的生物同位体，并导致具有良好体内活性的ARIs。体外和体内活性均通过染色质顺式2-甲基化和芳香族6,7-卤素取代而提高。对大鼠急性体内活性最佳的化合物进行了慢性体内活性比较。外消旋的6,7-二氯和6-氟-7-氯类似物18和23具有最高的组织水平和最佳的体内慢性活性。ARI活性对58和60、18和23的2R、4r对映体具有对映选择性。7-氯-6-氟-顺-4-羟基-2(R)-甲基-铬-4-乙酸（60）被选为1期临床试验，没有表现出类似山梨醇的过敏副作用。
The hypothesis that clinical side effects of the aldose reductase inhibitor (ARI) sorbinil were related to its hydantoin ring led to a bioisosteric analysis and replacement of the hydantoin by a spiro hydroxy acetic acid moiety as in 40. These hydroxy acids, compared to hydantoins, showed a similar potency increase on chroman 2-methyl substitution, a similar orthogonal relationship of acidic to aromatic moieties, and similar ARI enantioselectivity. In this series the six-membered spiro hydroxy acetic acid anion array is a bioisostere for a spiro hydantoin anion and leads to ARIs with excellent in vivo activity. In vitro and in vivo activity was improved over 40 by chroman cis 2-methylation as in 4 and by aromatic 6,7-halogen substitution. Compounds with the best acute in vivo activity in rats were compared for chronic in vivo activity. The highest tissue levels and best chronic in vivo activities were found in the racemic 6,7-dichloro and 6-fluoro-7-chloro analogues 18 and 23. ARI activity was enantioselective for 58 and 60, the 2R,4R-enantiomers of 18 and 23. 7-Chloro-6-fluoro-cis-4-hydroxy-2(R)-methyl-chroman-4-acetic acid (60) was selected for phase 1 clinical trials and did not exhibit sorbinil-like hypersensitivity side effects.