Lipinski C A, Aldinger C E, Beyer T A, Bordner J, Burdi D F, Bussolotti D L, Inskeep P B, Siegel T W
Central Research Division, Pfizer Inc., Groton, Connecticut 06340.
J Med Chem. 1992 Jun 12;35(12):2169-77. doi: 10.1021/jm00090a004.
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.
醛糖还原酶抑制剂（ARI）索比尼尔的临床副作用与其乙内酰脲环有关这一假说，引发了生物电子等排体分析，并如化合物40那样，用螺环羟基乙酸部分取代了乙内酰脲。与乙内酰脲相比，这些羟基酸在苯并二氢吡喃2-甲基取代时显示出相似的效价增加，酸性基团与芳香基团之间具有相似的正交关系，以及相似的ARI对映体选择性。在该系列中，六元螺环羟基乙酸阴离子阵列是螺环乙内酰脲阴离子的生物电子等排体，可产生具有优异体内活性的ARI。如化合物4那样，通过苯并二氢吡喃顺式2-甲基化以及芳香环6,7-卤代，化合物40的体外和体内活性得到了改善。比较了在大鼠中具有最佳急性体内活性的化合物的慢性体内活性。在外消旋的6,7-二氯和6-氟-7-氯类似物18和23中发现了最高的组织水平和最佳的慢性体内活性。ARI活性对18和23的2R,4R-对映体58和60具有对映体选择性。7-氯-6-氟-顺式-4-羟基-2(R)-甲基-苯并二氢吡喃-4-乙酸（60）被选用于1期临床试验，且未表现出索比尼尔样的过敏副作用。
