Design, synthesis, and biological evaluation of novel (1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)acetic acids as selective inhibitors for AKR1B1

Daisuke Minehira; Daisuke Takeda; Hirokazu Urata; Atsushi Kato; Isao Adachi; Xu Wang; Yuji Matsuya; Kenji Sugimoto; Mayuko Takemura; Satoshi Endo; Toshiyuki Matsunaga; Akira Hara; Jun Koseki; Kayo Narukawa; Shuichi Hirono; Naoki Toyooka

doi:10.1016/j.bmc.2011.10.073

Design, synthesis, and biological evaluation of novel (1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)acetic acids as selective inhibitors for AKR1B1

Bioorg Med Chem. 2012 Jan 1;20(1):356-67. doi: 10.1016/j.bmc.2011.10.073. Epub 2011 Nov 3.

Authors

Daisuke Minehira¹, Daisuke Takeda, Hirokazu Urata, Atsushi Kato, Isao Adachi, Xu Wang, Yuji Matsuya, Kenji Sugimoto, Mayuko Takemura, Satoshi Endo, Toshiyuki Matsunaga, Akira Hara, Jun Koseki, Kayo Narukawa, Shuichi Hirono, Naoki Toyooka

Affiliation

¹ Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.

PMID: 22104435
DOI: 10.1016/j.bmc.2011.10.073

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetates / chemical synthesis
Acetates / chemistry*
Acetates / pharmacology*
Aldehyde Reductase / antagonists & inhibitors*
Aldehyde Reductase / metabolism
Aldo-Keto Reductases
Binding Sites
Carbolines / chemical synthesis*
Carbolines / chemistry
Carbolines / isolation & purification
Carbolines / pharmacology*
Computer Simulation
Drug Design*
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Evodia / chemistry
Humans
Hydrogen Bonding
Kinetics
Protein Structure, Tertiary
Structure-Activity Relationship

Substances

(2-benzyl-6-carboxy-1-thioxo-1,2,3,4-tetrahydro-beta-carbolin-9-yl)acetic acid
Acetates
Carbolines
Enzyme Inhibitors
N2-(2-methylaminobenzoyl)tetrahydro-1H-pyrido(3,4-b)indol-1-one
AKR1B10 protein, human
Aldo-Keto Reductases
AKR1B1 protein, human
Aldehyde Reductase