Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
Bioorg Med Chem. 2012 Jan 1;20(1):356-67. doi: 10.1016/j.bmc.2011.10.073. Epub 2011 Nov 3.
New substituted (1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)acetic acids were designed as the inhibitor of AKR1B1 based upon the structure of rhetsinine, a minor alkaloidal component of Evodia rutaecarpa, and twenty derivatives were synthesized and evaluated. The most active compound of the series was (2-benzyl-6-methoxy-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)acetic acid (7m), which showed comparable inhibitory activity for AKR1B1 (IC(50)=0.15μM) with clinically used epalrestat (IC(50)=0.1μM). In the view of activity and selectivity, the most potent compound was (2-benzyl-6-carboxy-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)acetic acid (7t), which showed strong inhibitory effect (IC(50)=0.17μM) and very high selectivity for AKR1B1 against AKR1A1 (311:1) and AKR1B10 (253:1) compared with epalrestat.
新型取代的（1-硫代-1,2,3,4-四氢-β-咔啉-9-基）乙酸类化合物被设计为 AKR1B1 的抑制剂，其基于吴茱萸次碱的结构，吴茱萸次碱是吴茱萸 Evodia rutaecarpa 的一种次要生物碱成分，合成了二十个衍生物并对其进行了评估。该系列中最活跃的化合物是（2-苄基-6-甲氧基-1-硫代-1,2,3,4-四氢-β-咔啉-9-基）乙酸（7m），其对 AKR1B1 的抑制活性与临床使用的依帕司他（IC50=0.1μM）相当（IC50=0.15μM）。从活性和选择性来看，最有效的化合物是（2-苄基-6-羧基-1-硫代-1,2,3,4-四氢-β-咔啉-9-基）乙酸（7t），与依帕司他相比，其对 AKR1B1 具有很强的抑制作用（IC50=0.17μM），对 AKR1A1（311:1）和 AKR1B10（253:1）具有很高的选择性。
