title: 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.
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.
authors: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors: Daisuke
authors: D
authors: Minehira
authors: Daisuke
authors: D
authors: Takeda
authors: Hirokazu
authors: H
authors: Urata
authors: Atsushi
authors: A
authors: Kato
authors: Isao
authors: I
authors: Adachi
authors: Xu
authors: X
authors: Wang
authors: Yuji
authors: Y
authors: Matsuya
authors: Kenji
authors: K
authors: Sugimoto
authors: Mayuko
authors: M
authors: Takemura
authors: Satoshi
authors: S
authors: Endo
authors: Toshiyuki
authors: T
authors: Matsunaga
authors: Akira
authors: A
authors: Hara
authors: Jun
authors: J
authors: Koseki
authors: Kayo
authors: K
authors: Narukawa
authors: Shuichi
authors: S
authors: Hirono
authors: Naoki
authors: N
authors: Toyooka
mesh_terms: D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000074408:Aldo-Keto Reductases; D001665:Binding Sites; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D003198:Computer Simulation; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D032086:Evodia / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: C571778:(2-benzyl-6-carboxy-1-thioxo-1,2,3,4-tetrahydro-beta-carbolin-9-yl)acetic acid; D000085:Acetates; D002243:Carbolines; D004791:Enzyme Inhibitors; C539930:N2-(2-methylaminobenzoyl)tetrahydro-1H-pyrido(3,4-b)indol-1-one; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; C484670:AKR1B1 protein, human; D000449:Aldehyde Reductase