ChemInform Abstract: Novel, Highly Potent Aldose Reductase Inhibitors: (R)-(-)-2-(4-Bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo [1,2-a]pyrazine-4-spiro-3′-pyrrolidine-1,2′,3,5′-tetrone (AS-3201) and Its Congeners

Autor: Buichi Fujitani, Jun-Ichi Matsumoto, Makoto Murata, Toshiyuki Negoro, Akemi Kuromiya, Kenji Suzuki, Yoshiyuki Ono, Masanobu Komiya, Ueda Shozo
Rok vydání: 2010
Předmět:
Zdroj: ChemInform. 30
ISSN: 1522-2667
0931-7597
DOI: 10.1002/chin.199911179
Popis: A series of novel tetrahydropyrrolo[1,2-a]pyrazine derivatives were synthesized and evaluated as aldose reductase inhibitors (ARIs) on the basis of their abilities to inhibit porcine lens aldose reductase (AR) in vitro and to inhibit sorbitol accumulation in the sciatic nerve of streptozotocin-induced diabetic rats in vivo. Of these compounds, spirosuccinimide-fused tetrahydropyrrolo[1,2-a]pyrazine-1,3-dione derivatives showed significantly potent AR inhibitory activity. In the in vivo activity of these derivatives, 2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3‘-pyrrolidine-1,2‘,3,5‘-tetrone (23t) (SX-3030) showed the best oral activity. The enantiomers of 23t were synthesized, and the biological activities were evaluated. It was found that AR inhibitory activity resides in the (−)-enantiomer 43 (AS-3201), which was 10 times more potent in inhibition of the AR (IC50 = 1.5 × 10-8 M) and 500 times more potent in the in vivo activity (ED50 = 0.18 mg/kg/day for 5 days) than the...
Databáze: OpenAIRE
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